Prodrugs of NRF2 Activating Compounds and Uses Thereof

ABSTRACT

Aspects of the present disclosure include prodrugs of compounds that activate Nrf2. Such prodrugs find use in the treatment of autoimmune and inflammatory diseases and disorders, such as for example psoriasis and multiple sclerosis. Embodiments of the present disclosure also relate to pharmaceutical compositions that include these prodrugs, methods of using these prodrugs in the treatment of various diseases and disorders, processes for preparing these prodrugs and intermediates useful in these processes.

INTRODUCTION

Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 orNrf2, is a transcription factor that in humans is encoded by the NFE2L2gene. Nrf2 is a basic leucine zipper (bZIP) protein that regulates theexpression of antioxidant proteins that protect against oxidative damagetriggered by injury and inflammation.

Fumaric acid is an intermediate product of the citric acid cycle.Fumaric acid is a source of intracellular energy in the form ofadenosine triphosphate (ATP), and is generated by oxidation ofadenylsuccinate by the enzyme succinate dehydrogenase which is thenconverted to maleate by the enzyme fumarase. Fumaric acid esters (FAE),such as dimethylfumarate (DMF) have been used in the treatment ofpsoriasis and multiple sclerosis. After oral intake, DMF is rapidlyhydrolyzed by esterases to its metabolite monomethyl fumarate (MMF).

Glutathione (GSH) is an antioxidant that can be synthesized in the bodyfrom the amino acids L-cysteine, L-glutamic acid, and glycine.Glutathione can be in a reduced state (GSH) or an oxidized state(glutathione disulfide, GSSG). The reduced form of glutathione (GSH) canact as an antioxidant by scavenging reactive oxygen species.

Multiple sclerosis (MS), also known as disseminated sclerosis orencephalomyelitis disseminata, is an inflammatory disease in which theinsulating covers of nerve cells in the brain and spinal cord aredamaged. This damage disrupts the ability of parts of the nervous systemto communicate. The three main characteristics of MS are the formationof lesions in the central nervous system (also called plaques),inflammation, and the destruction of myelin sheaths of neurons. MS maybe caused by either destruction of the myelin sheaths of neurons by theimmune system or failure of the myelin-producing cells.

Psoriasis is a chronic relapsing/remitting immune-mediated skin diseasecharacterized by red, scaly patches, papules, and plaques. There arefive main types of psoriasis: plaque, guttate, inverse, pustular, anderythrodermic. Plaque psoriasis is the most common form and typicalsymptoms are red and white scaly patches on the top layer of the skin.Psoriasis is thought to be caused when the immune system mistakes normalskin cells for a pathogen, and secretes inflammatory chemical signals(cytokines) that cause overproduction of new skin cells.

SUMMARY

Aspects of the present disclosure include prodrugs of compounds thatactivate Nrf2. Such prodrugs may find use in the treatment of autoimmuneand inflammatory diseases and disorders, such as for example psoriasisand multiple sclerosis. Embodiments of the present disclosure alsorelate to pharmaceutical compositions that include these prodrugs,methods of using these prodrugs in the treatment of various diseases anddisorders, processes for preparing these prodrugs and intermediatesuseful in these processes.

Embodiments of the prodrugs are provided throughout the presentdisclosure. In certain embodiments, the prodrug is a compoundrepresented by the following formula (I):

wherein:

R² is selected from the group consisting of sulfonyl, carboxyl, carboxylester, and aminoacyl;

R³ is selected from the group consisting of an active agent, anantioxidant, an amino acid, an amino acid derivative, a peptide, and apeptide derivative;

R⁴ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;

X¹ and X² are each independently selected from N and CH, wherein atleast one of X¹ and X² is N; and

n is an integer from 1 to 6,

or a salt or a stereoisomer thereof.

In certain embodiments, R² is sulfonyl or carboxyl ester.

In certain embodiments, the compound is a compound of formula (II):

wherein:

R³ is selected from the group consisting of an active agent, anantioxidant, an amino acid, an amino acid derivative, a peptide, and apeptide derivative;

R⁴ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;

R⁵ is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, and substituted heteroaryl;

X¹ and X² are each independently selected from N and CH, wherein atleast one of X¹ and X² is N; and

n is an integer from 1 to 6,

or a salt or a stereoisomer thereof.

In certain embodiments, R⁵ is aryl or substituted aryl.

In certain embodiments, n is 1. In certain embodiments, n is 2.

In certain embodiments, R³ is glutathione. In certain embodiments, R³ isan amino acid or an amino acid derivative.

In certain embodiments, X¹ is N and X² is N. In certain embodiments, X¹is N and X² is CH.

In certain embodiments, the compound is:

In certain embodiments, the compound is an isolated compound having thestructure:

Aspects of the present disclosure include a pharmaceutical compositionthat includes a compound as described herein, and a pharmaceuticallyacceptable carrier.

Aspects of the present disclosure include a method of treating a diseaseor disorder in a subject in need thereof. The method includesadministering to the subject a pharmaceutically effective amount of acompound as described herein or a pharmaceutical composition asdescribed herein sufficient to treat the disease or disorder in thesubject, where the disease or disorder is an autoimmune disease or aninflammatory disease.

In certain embodiments, the disease or disorder is psoriasis or multiplesclerosis.

DETAILED DESCRIPTION

Aspects of the present disclosure include prodrugs of compounds thatactivate Nrf2. Such prodrugs may find use in the treatment of autoimmuneand inflammatory diseases and disorders, such as for example psoriasisand multiple sclerosis. Embodiments of the present disclosure alsorelate to pharmaceutical compositions that include these prodrugs,methods of using these prodrugs in the treatment of various diseases anddisorders, processes for preparing these prodrugs and intermediatesuseful in these processes.

The prodrugs and compounds described herein may contain one or morechiral centers and therefore, the embodiments are directed to racemicmixtures; pure stereoisomers (i.e., enantiomers or diastereomers);stereoisomer-enriched mixtures and the like unless otherwise indicated.When a particular stereoisomer is shown or named herein, it will beunderstood by those skilled in the art that minor amounts of otherstereoisomers may be present in the compositions unless otherwiseindicated, provided that the desired utility of the composition as awhole is not eliminated by the presence of such other isomers.

Before the present invention is further described, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

It must be noted that as used herein and in the appended claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is specifically contemplated. The upper and lower limitsof these smaller ranges may independently be included in the smallerranges, and are also encompassed within the invention, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the invention.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

Except as otherwise noted, the methods and techniques of the presentembodiments are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, NewYork: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith andMarch, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, Fifth Edition, Wiley-Interscience, 2001; or Vogel, A Textbookof Practical Organic Chemistry, Including Qualitative Organic Analysis,Fourth Edition, New York: Longman, 1978.

The nomenclature used herein to name the subject compounds isillustrated in the Examples herein. This nomenclature has generally beenderived using the commercially-available AutoNom software (MDL, SanLeandro, Calif.). Terms

The following terms have the following meanings unless otherwiseindicated. Any undefined terms have their art recognized meanings.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupshaving from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms.This term includes, by way of example, linear and branched hydrocarbylgroups such as methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl (CH₃CH₂CH₂—),isopropyl ((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl ((CH₃)₂CHCH₂—),sec-butyl ((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—), n-pentyl(CH₃CH₂CH₂CH₂CH₂—), and neopentyl ((CH₃)₃CCH₂—).

The term “substituted alkyl” refers to an alkyl group as defined hereinwherein one or more carbon atoms in the alkyl chain (except the C₁carbon atom) have been optionally replaced with a heteroatom such as—O—, —N—, —S—, —S(O)_(n)— (where n is 0 to 2), —NR— (where R is hydrogenor alkyl) and having from 1 to 5 substituents selected from the groupconsisting of alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano,halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy,thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substitutedthioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, —SO₂-aryl, —SO₂-heteroaryl, and—NR^(a)R^(b), wherein R′ and R″ may be the same or different and arechosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.

“Alkylene” refers to divalent aliphatic hydrocarbyl groups preferablyhaving from 1 to 6 and more preferably 1 to 3 carbon atoms that areeither straight-chained or branched, and which are optionallyinterrupted with one or more groups selected from —O—, —NR¹⁰—,—NR¹⁰C(O)—, —C(O)NR¹⁰— and the like. This term includes, by way ofexample, methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene(—CH₂CH₂CH₂—), iso-propylene (—CH₂CH(CH₃)—), (—C(CH₃)₂CH₂CH₂—),(—C(CH₃)₂CH₂C(O)—), (—C(CH₃)₂CH₂C(O)NH—), (—CH(CH₃)CH₂—), and the like.

“Substituted alkylene” refers to an alkylene group having from 1 to 3hydrogens replaced with substituents as described for carbons in thedefinition of “substituted” below.

The term “alkane” refers to alkyl group and alkylene group, as definedherein.

The term “alkylaminoalkyl”, “alkylaminoalkenyl” and “alkylaminoalkynyl”refers to the groups R′NHR″—where R′ is alkyl group as defined hereinand R″ is alkylene, alkenylene or alkynylene group as defined herein.

The term “alkaryl” or “aralkyl” refers to the groups -alkylene-aryl and-substituted alkylene-aryl where alkylene, substituted alkylene and arylare defined herein.

“Alkoxy” refers to the group —O-alkyl, wherein alkyl is as definedherein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like. Theterm “alkoxy” also refers to the groups alkenyl-O—, cycloalkyl-O—,cycloalkenyl-O—, and alkynyl-O—, where alkenyl, cycloalkyl,cycloalkenyl, and alkynyl are as defined herein.

The term “substituted alkoxy” refers to the groups substituted alkyl-O—,substituted alkenyl-O—, substituted cycloalkyl-O—, substitutedcycloalkenyl-O—, and substituted alkynyl-O— where substituted alkyl,substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyland substituted alkynyl are as defined herein.

The term “alkoxyamino” refers to the group —NH-alkoxy, wherein alkoxy isdefined herein.

The term “haloalkoxy” refers to the groups alkyl-O— wherein one or morehydrogen atoms on the alkyl group have been substituted with a halogroup and include, by way of examples, groups such as trifluoromethoxy,and the like.

The term “haloalkyl” refers to a substituted alkyl group as describedabove, wherein one or more hydrogen atoms on the alkyl group have beensubstituted with a halo group. Examples of such groups include, withoutlimitation, fluoroalkyl groups, such as trifluoromethyl, difluoromethyl,trifluoroethyl and the like.

The term “alkylalkoxy” refers to the groups -alkylene-O-alkyl,alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, andsubstituted alkylene-O-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.

The term “alkylthioalkoxy” refers to the group -alkylene-S-alkyl,alkylene-S-substituted alkyl, substituted alkylene-S-alkyl andsubstituted alkylene-S-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.

“Alkenyl” refers to straight chain or branched hydrocarbyl groups havingfrom 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and havingat least 1 and preferably from 1 to 2 sites of double bond unsaturation.This term includes, by way of example, bi-vinyl, allyl, andbut-3-en-1-yl. Included within this term are the cis and trans isomersor mixtures of these isomers.

The term “substituted alkenyl” refers to an alkenyl group as definedherein having from 1 to 5 substituents, or from 1 to 3 substituents,selected from alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO— substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

“Alkynyl” refers to straight or branched monovalent hydrocarbyl groupshaving from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms andhaving at least 1 and preferably from 1 to 2 sites of triple bondunsaturation. Examples of such alkynyl groups include acetylenyl(—C≡CH), and propargyl (—CH₂C≡CH).

The term “substituted alkynyl” refers to an alkynyl group as definedherein having from 1 to 5 substituents, or from 1 to 3 substituents,selected from alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO— substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl, and —SO₂-heteroaryl.

“Alkynyloxy” refers to the group —O-alkynyl, wherein alkynyl is asdefined herein. Alkynyloxy includes, by way of example, ethynyloxy,propynyloxy, and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substitutedheteroaryl-C(O)—, heterocyclyl-C(O)—, and substitutedheterocyclyl-C(O)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein. For example, acylincludes the “acetyl” group CH₃C(O)—

“Acylamino” refers to the groups —NR²⁰C(O)alkyl, —NR²⁰C(O) substitutedalkyl, N R²⁰C(O)cycloalkyl, —NR²⁰C(O) substituted cycloalkyl,—NR²⁰C(O)cycloalkenyl, —NR²⁰C(O) substituted cycloalkenyl,—NR²⁰C(O)alkenyl, —NR²⁰C(O) substituted alkenyl, —NR²⁰C(O)alkynyl,—NR²⁰C(O) substituted alkynyl, —NR²⁰C(O)aryl, —NR²⁰C(O) substitutedaryl, —NR²⁰C(O)heteroaryl, —NR²⁰C(O) substituted heteroaryl,—NR²⁰C(O)heterocyclic, and —NR²⁰C(O) substituted heterocyclic, whereinR²⁰ is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Aminocarbonyl” or the term “aminoacyl” refers to the group—C(O)NR²¹R²², wherein R²¹ and R²² independently are selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic and where R²¹ and R²² are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Aminocarbonylamino” refers to the group —NR²¹C(O)NR²²R²³ where R²¹,R²², and R²³ are independently selected from hydrogen, alkyl, aryl orcycloalkyl, or where two R groups are joined to form a heterocyclylgroup.

The term “alkoxycarbonylamino” refers to the group —NRC(O)OR where eachR is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl,or heterocyclyl wherein alkyl, substituted alkyl, aryl, heteroaryl, andheterocyclyl are as defined herein.

The term “acyloxy” refers to the groups alkyl-C(O)O—, substitutedalkyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—,aryl-C(O)O—, heteroaryl-C(O)O—, and heterocyclyl-C(O)O— wherein alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl,and heterocyclyl are as defined herein.

“Aminosulfonyl” refers to the group —SO₂NR²¹R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic and where R²¹ and R²²are optionally joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group and alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Sulfonylamino” refers to the group —NR²¹SO₂R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the atoms bound thereto to forma heterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from6 to 18 carbon atoms having a single ring (such as is present in aphenyl group) or a ring system having multiple condensed rings (examplesof such aromatic ring systems include naphthyl, anthryl and indanyl)which condensed rings may or may not be aromatic, provided that thepoint of attachment is through an atom of an aromatic ring. This termincludes, by way of example, phenyl and naphthyl. Unless otherwiseconstrained by the definition for the aryl substituent, such aryl groupscan optionally be substituted with from 1 to 5 substituents, or from 1to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,substituted alkoxy, substituted alkenyl, substituted alkynyl,substituted cycloalkyl, substituted cycloalkenyl, amino, substitutedamino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy,heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl and trihalomethyl.

“Aryloxy” refers to the group —O-aryl, wherein aryl is as definedherein, including, by way of example, phenoxy, naphthoxy, and the like,including optionally substituted aryl groups as also defined herein.

“Amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl,substituted alkynyl, aryl, heteroaryl, and heterocyclyl provided that atleast one R is not hydrogen.

The term “azido” refers to the group —N₃.

“Carboxyl,” “carboxy” or “carboxylate” refers to —CO₂H or salts thereof.

“Carboxyl ester” or “carboxy ester” or the terms “carboxyalkyl” or“carboxylalkyl” refers to the groups —C(O)O-alkyl, —C(O)O-substitutedalkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl,—C(O)O-substituted alkynyl, —C(O)O-aryl, —C(O)O-substituted aryl,—C(O)O-cycloalkyl, —C(O)O-substituted cycloalkyl, —C(O)O-cycloalkenyl,—C(O)O-substituted cycloalkenyl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, —C(O)O-heterocyclic, and —C(O)O-substituted heterocyclic,wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“(Carboxyl ester)oxy” or “carbonate” refers to the groups—O—C(O)O-alkyl, —O—C(O)O-substituted alkyl, —O—C(O)O-alkenyl,—O—C(O)O-substituted alkenyl, —O—C(O)O— alkynyl, —O—C(O)O-substitutedalkynyl, —O—C(O)O-aryl, —O—C(O)O-substituted aryl, —O—C(O)O— cycloalkyl,—O—C(O)O-substituted cycloalkyl, —O—C(O)O-cycloalkenyl,—O—C(O)O-substituted cycloalkenyl, —O—C(O)O-heteroaryl,—O—C(O)O-substituted heteroaryl, —O—C(O)O-heterocyclic, and—O—C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Cyano” or “nitrile” refers to the group —CN.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atomshaving single or multiple cyclic rings including fused, bridged, andspiro ring systems. Examples of suitable cycloalkyl groups include, forinstance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyland the like. Such cycloalkyl groups include, by way of example, singlering structures such as cyclopropyl, cyclobutyl, cyclopentyl,cyclooctyl, and the like, or multiple ring structures such asadamantanyl, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups havingfrom 1 to 5 substituents, or from 1 to 3 substituents, selected fromalkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

“Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to10 carbon atoms having single or multiple rings and having at least onedouble bond and preferably from 1 to 2 double bonds.

The term “substituted cycloalkenyl” refers to cycloalkenyl groups havingfrom 1 to 5 substituents, or from 1 to 3 substituents, selected fromalkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino,substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano,halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy,thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substitutedthioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

“Cycloalkynyl” refers to non-aromatic cycloalkyl groups of from 5 to 10carbon atoms having single or multiple rings and having at least onetriple bond.

“Cycloalkoxy” refers to —O-cycloalkyl.

“Cycloalkenyloxy” refers to —O-cycloalkenyl.

“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Heteroaryl” refers to an aromatic group of from 1 to 15 carbon atoms,such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected fromthe group consisting of oxygen, nitrogen, and sulfur within the ring.Such heteroaryl groups can have a single ring (such as, pyridinyl (i.e.,pyridyl), imidazolyl or furyl) or multiple condensed rings in a ringsystem (for example as in groups such as, indolizinyl, quinolinyl,benzofuran, benzimidazolyl or benzothienyl), wherein at least one ringwithin the ring system is aromatic and at least one ring within the ringsystem is aromatic, provided that the point of attachment is through anatom of an aromatic ring. In certain embodiments, the nitrogen and/orsulfur ring atom(s) of the heteroaryl group are optionally oxidized toprovide for the N-oxide (N→O), sulfinyl, or sulfonyl moieties. This termincludes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl,and furanyl. Unless otherwise constrained by the definition for theheteroaryl substituent, such heteroaryl groups can be optionallysubstituted with 1 to 5 substituents, or from 1 to 3 substituents,selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkoxy, substituted alkenyl, substituted alkynyl, substitutedcycloalkyl, substituted cycloalkenyl, amino, substituted amino,aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy,heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl, andtrihalomethyl.

The term “heteroaralkyl” refers to the groups -alkylene-heteroaryl wherealkylene and heteroaryl are defined herein. This term includes, by wayof example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.

“Heteroaryloxy” refers to —O-heteroaryl.

“Heterocycle,” “heterocyclic,” “heterocycloalkyl,” and “heterocyclyl”refer to a saturated or unsaturated group having a single ring ormultiple condensed rings, including fused bridged and spiro ringsystems, and having from 3 to 20 ring atoms, including 1 to 10 heteroatoms. These ring atoms are selected from the group consisting ofnitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or moreof the rings can be cycloalkyl, aryl, or heteroaryl, provided that thepoint of attachment is through the non-aromatic ring. In certainembodiments, the nitrogen and/or sulfur atom(s) of the heterocyclicgroup are optionally oxidized to provide for the N-oxide, —S(O)—, or—SO₂— moieties.

Examples of heterocycles and heteroaryls include, but are not limitedto, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine,tetrahydrofuranyl, and the like.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5, or from 1 to 3 substituents, selected from alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl,—SO₂-heteroaryl, and fused heterocycle.

“Heterocyclyloxy” refers to the group —O-heterocyclyl.

The term “heterocyclylthio” refers to the group heterocyclic-S—.

The term “heterocyclene” refers to the diradical group formed from aheterocycle, as defined herein.

The term “hydroxyamino” refers to the group —NHOH.

“Nitro” refers to the group —NO₂.

“Oxo” refers to the atom (═O).

“Sulfonyl” refers to the group —SO₂-alkyl, —SO₂-substituted alkyl,—SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-cycloalkyl,—SO₂-substituted cycloalkyl, —SO₂-cycloalkenyl, —SO₂— substitutedcycloalkenyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, —SO₂-heterocyclic, and —SO₂-substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein. Sulfonyl includes, by way ofexample, methyl-SO₂—, phenyl-SO₂—, and 4-methylphenyl-SO₂—.

“Sulfonyloxy” refers to the group —OSO₂-alkyl, —OSO₂-substituted alkyl,—OSO₂-alkenyl, —OSO₂-substituted alkenyl, —OSO₂-cycloalkyl,—OSO₂-substituted cycloalkyl, —OSO₂-cycloalkenyl, —OSO₂-substitutedcylcoalkenyl, —OSO₂-aryl, —OSO₂-substituted aryl, —OSO₂-heteroaryl,—OSO₂-substituted heteroaryl, —OSO₂-heterocyclic, and —OSO₂ substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein.

The term “aminocarbonyloxy” refers to the group —OC(O)NRR where each Ris independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl,or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl andheterocyclic are as defined herein.

“Thiol” refers to the group —SH.

“Thioxo” or the term “thioketo” refers to the atom (═S).

“Alkylthio” or the term “thioalkoxy” refers to the group —S-alkyl,wherein alkyl is as defined herein. In certain embodiments, sulfur maybe oxidized to —S(O)—. The sulfoxide may exist as one or morestereoisomers.

The term “substituted thioalkoxy” refers to the group —S-substitutedalkyl.

The term “thioaryloxy” refers to the group aryl-S— wherein the arylgroup is as defined herein including optionally substituted aryl groupsalso defined herein.

The term “thioheteroaryloxy” refers to the group heteroaryl-S— whereinthe heteroaryl group is as defined herein including optionallysubstituted aryl groups as also defined herein.

The term “thioheterocyclooxy” refers to the group heterocyclyl-S—wherein the heterocyclyl group is as defined herein including optionallysubstituted heterocyclyl groups as also defined herein.

The term “tosyl” refers to the group

The wavy line indicates the bond through which the tosyl group isattached to the remainder of the molecule.

In addition to the disclosure herein, the term “substituted,” when usedto modify a specified group or radical, can also mean that one or morehydrogen atoms of the specified group or radical are each, independentlyof one another, replaced with the same or different substituent groupsas defined below.

In addition to the groups disclosed with respect to the individual termsherein, substituent groups for substituting for one or more hydrogens(any two hydrogens on a single carbon can be replaced with ═O, ═NR⁷⁰,═N—OR⁷⁰, ═N₂ or ═S) on saturated carbon atoms in the specified group orradical are, unless otherwise specified, —R⁶⁰, halo, ═O, —OR⁷⁰, —SR⁷⁰,—NR⁸⁰R⁸⁰, trihalomethyl, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —SO₂R⁷⁰,—SO₂ ⁻M⁺, —SO₂OR⁷⁰, —OSO₂R⁷⁰, —OSO₂O⁻M⁺, —OSO₂OR⁷⁰, —P(O)(O⁻)₂(M⁺)₂,—P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰,—C(O)O⁻M⁺, —C(O)OR⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰,—OC(O)R⁷⁰, —OC(S)R⁷⁰, —OC(O)O⁻M⁺, —OC(O)OR⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰,—NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰ isselected from the group consisting of optionally substituted alkyl,cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl and heteroarylalkyl, each R⁷⁰ is independentlyhydrogen or R⁶⁰; each R⁸⁰ is independently R⁷⁰ or alternatively, twoR⁸⁰'s, taken together with the nitrogen atom to which they are bonded,form a 5-, 6- or 7-membered heterocycloalkyl which may optionallyinclude from 1 to 4 of the same or different additional heteroatomsselected from the group consisting of O, N and S, of which N may have —Hor C₁-C₃ alkyl substitution; and each M⁺ is a counter ion with a netsingle positive charge. Each M⁺ may independently be, for example, analkali ion, such as K⁺, Na⁺, Li⁺; an ammonium ion, such as ⁺N(R⁶⁰)₄; oran alkaline earth ion, such as [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or[Ba²⁺]_(0.5) (“subscript 0.5 means that one of the counter ions for suchdivalent alkali earth ions can be an ionized form of a compound of theinvention and the other a typical counter ion such as chloride, or twoionized compounds disclosed herein can serve as counter ions for suchdivalent alkali earth ions, or a doubly ionized compound of theinvention can serve as the counter ion for such divalent alkali earthions). As specific examples, —NR⁸⁰R⁸⁰ is meant to include —NH₂,—NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl andN-morpholinyl.

In addition to the disclosure herein, substituent groups for hydrogenson unsaturated carbon atoms in “substituted” alkene, alkyne, aryl andheteroaryl groups are, unless otherwise specified, —R⁶⁰, halo, —O⁻M⁺,—OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰, trihalomethyl, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺,—OSO₃R⁷⁰, —PO₃ ⁻²(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰,—C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OC₂R⁷⁰, —OC(S)OR⁷⁰,—NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰,R⁷⁰, R⁸⁰ and M⁺ are as previously defined, provided that in case ofsubstituted alkene or alkyne, the substituents are not —O⁻M⁺, —OR⁷⁰,—SR⁷⁰, or —S⁻M⁺.

In addition to the groups disclosed with respect to the individual termsherein, substituent groups for hydrogens on nitrogen atoms in“substituted” heteroalkyl and cycloheteroalkyl groups are, unlessotherwise specified, —R⁶⁰, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰,trihalomethyl, —CF₃, —CN, —NO, —NO₂, —S(O)₂R⁷⁰, —S(O)₂O⁻M⁺, —S(O)₂OR⁷⁰,—OS(O)₂R⁷⁰, —OS(O)₂O⁻M⁺, —OS(O)₂OR⁷⁰, —P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺,—P(O)(OR⁷⁰)(OR⁷⁰), —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —C(O)OR⁷⁰,—C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰,—OC(O)OR⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰C(O)OR⁷⁰,—NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and—NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ are as previouslydefined.

In addition to the disclosure herein, in a certain embodiment, a groupthat is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3substituents, 1 or 2 substituents, or 1 substituent.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,which is further substituted with a substituted aryl group, etc.) arenot intended for inclusion herein. In such cases, the maximum number ofsuch substitutions is three. For example, serial substitutions ofsubstituted aryl groups specifically contemplated herein are limited tosubstituted aryl-(substituted aryl)-substituted aryl.

Unless indicated otherwise, the nomenclature of substituents that arenot explicitly defined herein are arrived at by naming the terminalportion of the functionality followed by the adjacent functionalitytoward the point of attachment. For example, the substituent“arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.

As to any of the groups disclosed herein which contain one or moresubstituents, it is understood, of course, that such groups do notcontain any substitution or substitution patterns which are stericallyimpractical and/or synthetically non-feasible. In addition, the subjectcompounds include all stereochemical isomers arising from thesubstitution of these compounds.

The term “pharmaceutically acceptable salt” means a salt which isacceptable for administration to a patient, such as a mammal (salts withcounterions having acceptable mammalian safety for a given dosageregime). Such salts can be derived from pharmaceutically acceptableinorganic or organic bases and from pharmaceutically acceptableinorganic or organic acids. “Pharmaceutically acceptable salt” refers topharmaceutically acceptable salts of a compound, which salts are derivedfrom a variety of organic and inorganic counter ions well known in theart and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, formate, tartrate, besylate,mesylate, acetate, maleate, oxalate, and the like.

The term “salt thereof” means a compound formed when a proton of an acidis replaced by a cation, such as a metal cation or an organic cation andthe like. Where applicable, the salt is a pharmaceutically acceptablesalt, although this is not required for salts of intermediate compoundsthat are not intended for administration to a patient. By way ofexample, salts of the present compounds include those wherein thecompound is protonated by an inorganic or organic acid to form a cation,with the conjugate base of the inorganic or organic acid as the anioniccomponent of the salt.

“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of the solute. The solvent can be an organiccompound, an inorganic compound, or a mixture of both. Some examples ofsolvents include, but are not limited to, methanol,N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.When the solvent is water, the solvate formed is a hydrate.

“Stereoisomer” and “stereoisomers” refer to compounds that have sameatomic connectivity but different atomic arrangement in space.Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers,and diastereomers.

“Tautomer” refers to alternate forms of a molecule that differ only inelectronic bonding of atoms and/or in the position of a proton, such asenol-keto and imine-enamine tautomers, or the tautomeric forms ofheteroaryl groups containing a —N═C(H)—NH— ring atom arrangement, suchas pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. Aperson of ordinary skill in the art would recognize that othertautomeric ring atom arrangements are possible.

It will be appreciated that the term “or a salt or solvate orstereoisomer thereof” is intended to include all permutations of salts,solvates and stereoisomers, such as a solvate of a pharmaceuticallyacceptable salt of a stereoisomer of subject compound.

“Pharmaceutically effective amount” and “therapeutically effectiveamount” refer to an amount of a compound sufficient to treat a specifieddisorder or disease or one or more of its symptoms and/or to prevent theoccurrence of the disease or disorder. For example, in reference totumorigenic proliferative disorders, a pharmaceutically ortherapeutically effective amount comprises an amount sufficient to,among other things, cause the tumor to shrink or decrease the growthrate of the tumor.

“Patient” refers to human and non-human subjects, especially mammaliansubjects.

The term “treating” or “treatment” as used herein means the treating ortreatment of a disease or medical condition in a patient, such as amammal (particularly a human) that includes: (a) preventing the diseaseor medical condition from occurring, such as, prophylactic treatment ofa subject; (b) ameliorating the disease or medical condition, such as,eliminating or causing regression of the disease or medical condition ina patient; (c) suppressing the disease or medical condition, for exampleby, slowing or arresting the development of the disease or medicalcondition in a patient; or (d) alleviating a symptom of the disease ormedical condition in a patient.

The terms “polypeptide,” “peptide,” and “protein” are usedinterchangeably herein to refer to a polymeric form of amino acids ofany length. The terms “polypeptide derivative,” “peptide derivative,”and “protein derivative” can include genetically coded and non-codedamino acids, chemically or biochemically modified or derivatized aminoacids, and polypeptides having modified peptide backbones.

The terms “amino acid analog,” “unnatural amino acid,” “amino acidderivative,” and the like may be used interchangeably, and include aminoacid-like compounds that are similar in structure and/or overall shapeto one or more amino acids commonly found in naturally occurringproteins (e.g., Ala or A, Cys or C, Asp or D, Glu or E, Phe or F, Gly orG, His or H, Ile or I, Lys or K, Leu or L, Met or M, Asn or N, Pro or P,Gln or Q, Arg or R, Ser or S, Thr or T, Val or V, Trp or W, Tyr or Y).Amino acid derivatives also include natural amino acids with modifiedside chains or backbones. Amino acid derivatives also include amino acidanalogs with the same stereochemistry as in the naturally occurringD-form, as well as the L-form of amino acid analogs. In some instances,the amino acid derivatives share backbone structures, and/or the sidechain structures of one or more natural amino acids, with difference(s)being one or more modified groups in the molecule. Such modification mayinclude, but is not limited to, substitution of an atom (such as N) fora related atom (such as S), addition of a group (such as acyl, acetyl,methyl, or hydroxyl, etc.) or an atom (such as Cl or Br, etc.), deletionof a group, substitution of a covalent bond (single bond for doublebond, etc.), or combinations thereof. For example, amino acid analogsmay include N-acetyl amino acid derivatives, and the like.Representative Embodiments

The following substituents and values are intended to providerepresentative examples of various aspects and embodiments. Theserepresentative values are intended to further define and illustrate suchaspects and embodiments and are not intended to exclude otherembodiments or to limit the scope of the present disclosure. In thisregard, the representation that a particular value or substituent ispreferred is not intended in any way to exclude other values orsubstituents from the present disclosure unless specifically indicated.

Embodiments of the present disclosure include prodrugs of compounds thatactivate Nrf2.

The term “prodrug” refers to a derivative of an active compound (e.g., adrug or active agent) that undergoes a transformation under theconditions of use, such as within the body, to release the activecompound. Prodrugs may be, but are not necessarily, pharmacologicallyinactive until converted into the active drug. In some cases, prodrugsare pharmacologically inactive until converted into the active drug. Incertain cases, compounds that include a progroup may facilitate removalof the progroup at a desired site of action for the pharmaceuticallyactive form of the compound, or after a desired amount of time afteradministration of the compound (e.g., delayed release formulations,controlled release formulations, and the like). A wide variety ofprogroups, as well as the resultant promoieties, suitable for maskingfunctional groups in the active drugs to yield prodrugs may be used. Forexample, a hydroxyl functional group can be masked as a sulfonate, esteror carbonate promoiety, which can be hydrolyzed in vivo to provide thehydroxyl group. An amino functional group can be masked as an amide,carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl promoiety,which can be hydrolyzed in vivo to provide the amino group. A carboxylgroup can be masked as an ester (including silyl esters and thioesters),amide or hydrazide promoiety, which can be hydrolyzed in vivo to providethe carboxyl group. Other specific examples of suitable progroups andtheir respective promoieties will be apparent to those of skill in theart.

In some instances, prodrugs may be obtained by masking a functionalgroup in the drug believed to be in part required for activity with aprogroup to form a promoiety which undergoes a transformation, such ascleavage, under the specified conditions of use to release the activedrug. The cleavage of the promoiety can proceed spontaneously, such asby way of a hydrolysis reaction, or it can be catalyzed or induced byanother agent, such as by an enzyme, by light, by acid, or by a changeof or exposure to a physical or environmental parameter, such as achange of temperature. The agent can be endogenous to the conditions ofuse, such as an enzyme present in the cells to which the prodrug isadministered or the acidic conditions of the stomach, or it can besupplied exogenously. For example, in certain cases, compounds thatinclude a progroup may facilitate an increase in gastrointestinalpermeability, an increase in gastrointestinal absorption, and/or anincrease in solubility of the compound.

In certain embodiments, a prodrug can include a conjugate of two or moremoieties. For example, a prodrug can include a conjugate of two (ormore) active agents, such as a conjugate of an active agent (e.g., aNrf2 activating compound) to a second moiety (e.g., a second activeagent, an antioxidant, an amino acid, an amino acid derivative, apeptide, or a peptide derivative). The second moiety can have a desiredbiological activity in the subject to which the prodrug is administered.As such, a prodrug that is a conjugate of two (or more) active agentscan undergo a transformation, such as a cleavage or hydrolysis reaction,at a desired site of action such that two (or more) pharmaceuticallyactive agents are released at the site of action. In certainembodiments, prodrugs of the present disclosure are conjugates of twoactive agents that may be used for synergistic treatment of a particulartargeted disease or condition. For example, prodrugs of the presentdisclosure may include a conjugate of an Nrf2 activating compound and asecond moiety. The second moiety may be an active agent that also has adesired biological activity, such as a biological activity useful forthe treatment of a disease or condition that is also treated with theNrf2 activating compound released from the same prodrug as the secondmoiety.

Without being bound to any particular mechanistic theory, someembodiments of prodrugs of the present disclosure are adducts, such as aMichael addition adduct. Under the conditions of use, such as whenadministered to a subject, the Michael addition adduct prodrug mayundergo a retro-Michael reaction to release the Michael acceptorcompound and the Michael donor compound. The Michael adduct prodrug canbe an adduct of an active agent (e.g., a Nrf2 activating compound) and asecond moiety. As described above, the second moiety can be a moietysuch as a second active agent, an antioxidant, an amino acid, an aminoacid derivative, a peptide, or a peptide derivative, where the secondmoiety has a desired biological activity in the subject to which theprodrug is administered. For example, as indicated above, the secondmoiety may be an active agent that also has a desired biologicalactivity, such as a biological activity useful for the treatment of adisease or condition that is also treated with the Nrf2 activatingcompound released from the same prodrug as the second moiety. In certainembodiments, prodrugs of the present disclosure release two activeagents, such as a Nrf2 activating compound and a second moiety, wherethe two active agents may be used for synergistic treatment of aparticular targeted disease or condition.

As described above, the compounds released by the prodrug at the desiredsite of action can include a Nrf2 activating compound. By “activating”is meant that a compound selectively increases the activity of aparticular target. In some cases, an activating compound may also bereferred to as an “agonist”. For example, in some embodiments, a subjectNrf2 activating compound selectively increases the activity of Nrf2, ascompared to the activity of Nrf2 in the absence of the compound. Forexample, in some embodiments, a subject Nrf2 activating compoundincreases the activity of Nrf2 by 5% or more, e.g., by 10% or more, 15%or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% ormore, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more,70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% ormore, or 100% or more, as compared to the activity of Nrf2 in theabsence of the compound.

Additional description of the types of Nrf2 activating compounds thatfind use in the prodrugs disclosed herein is found in U.S. Pat. Nos.9,475,781; 9,845,307; and 9,845,311, the disclosures of which areincorporated herein by reference.

The prodrugs of the present disclosure include compounds of the formulaeshown below. Pharmaceutical compositions of the prodrugs and methodsinvolving the prodrugs of the present disclosure also use compounds ofthe following formulae.

Formula I

Embodiments of the presently disclosed compounds are represented by thefollowing formula (I):

wherein:

R² is selected from the group consisting of sulfonyl, carboxyl, carboxylester, and aminoacyl;

R³ is selected from the group consisting of an active agent, anantioxidant, an amino acid, an amino acid derivative, a peptide, and apeptide derivative;

R⁴ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;

X¹ and X² are each independently selected from N and CH, wherein atleast one of X¹ and X² is N; and

n is an integer from 1 to 6,

or a salt or a stereoisomer thereof.

In certain embodiments, R² is sulfonyl, carboxyl, carboxyl ester, oraminoacyl. In certain embodiments, R² is sulfonyl. In certainembodiments, R² is carboxyl. In certain embodiments, R² is carboxylester. In certain embodiments, R² is aminoacyl. Additional descriptionregarding the R² substituent is provided in the sections below.

In certain embodiments, R³ is an active agent, an antioxidant, an aminoacid, an amino acid derivative, a peptide, or a peptide derivative. Incertain embodiments, R³ is an active agent. In certain embodiments, R³is an antioxidant. In certain embodiments, R³ is an amino acid. Incertain embodiments, R³ is an amino acid derivative. In certainembodiments, R³ is a peptide. In certain embodiments, R³ is a peptidederivative. Additional description regarding the R³ substituent isprovided in the sections below.

In certain embodiments, X¹ and X² are each independently selected from Nand CH, where at least one of X¹ and X² is N. In some instances, X¹ is Nand X² is N. In some instances, X¹ is N and X² is CH. In some instances,X¹ is CH and X² is N.

In certain embodiments, n is an integer from 1 to 6. In certainembodiments, n is 1. In certain embodiments, n is 2. In certainembodiments, n is 3. In certain embodiments, n is 4. In certainembodiments, n is 5. In certain embodiments, n is 6.

Embodiments of the R⁴ substituent are described in more detail below.

Formula Ia & Formula Ib

In certain embodiments, the compounds of formula (I) include compoundswhere X¹ is N and X² is N. As such, compounds of the present disclosuremay be represented by the following formula (Ia):

wherein

R² is selected from the group consisting of sulfonyl, carboxyl, carboxylester, and aminoacyl;

R³ is selected from the group consisting of an active agent, anantioxidant, an amino acid, an amino acid derivative, a peptide, and apeptide derivative;

R⁴ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; and

n is an integer from 1 to 6,

or a salt or a stereoisomer thereof.

In certain embodiments, R² is sulfonyl, carboxyl, carboxyl ester, oraminoacyl. In certain embodiments, R² is sulfonyl. In certainembodiments, R² is carboxyl. In certain embodiments, R² is carboxylester. In certain embodiments, R² is aminoacyl. Additional descriptionregarding the R² substituent is provided in the sections below.

In certain embodiments, R³ is an active agent, an antioxidant, an aminoacid, an amino acid derivative, a peptide, or a peptide derivative. Incertain embodiments, R³ is an active agent. In certain embodiments, R³is an antioxidant. In certain embodiments, R³ is an amino acid. Incertain embodiments, R³ is an amino acid derivative. In certainembodiments, R³ is a peptide. In certain embodiments, R³ is a peptidederivative. Additional description regarding the R³ substituent isprovided in the sections below.

In certain embodiments, n is an integer from 1 to 6. In certainembodiments, n is 1. In certain embodiments, n is 2. In certainembodiments, n is 3. In certain embodiments, n is 4. In certainembodiments, n is 5. In certain embodiments, n is 6.

Embodiments of the R⁴ substituent are described in more detail below.

In certain embodiments, the compounds of formula (I) include compoundswhere X¹ is N and X² is CH. As such, compounds of the present disclosuremay be represented by the following formula (Ib):

wherein

R² is selected from the group consisting of sulfonyl, carboxyl, carboxylester, and aminoacyl;

R³ is selected from the group consisting of an active agent, anantioxidant, an amino acid, an amino acid derivative, a peptide, and apeptide derivative;

R⁴ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; and

n is an integer from 1 to 6,

or a salt or a stereoisomer thereof.

In certain embodiments, R² is sulfonyl, carboxyl, carboxyl ester, oraminoacyl. In certain embodiments, R² is sulfonyl. In certainembodiments, R² is carboxyl. In certain embodiments, R² is carboxylester. In certain embodiments, R² is aminoacyl. Additional descriptionregarding the R² substituent is provided in the sections below.

In certain embodiments, R³ is an active agent, an antioxidant, an aminoacid, an amino acid derivative, a peptide, or a peptide derivative. Incertain embodiments, R³ is an active agent. In certain embodiments, R³is an antioxidant. In certain embodiments, R³ is an amino acid. Incertain embodiments, R³ is an amino acid derivative. In certainembodiments, R³ is a peptide. In certain embodiments, R³ is a peptidederivative. Additional description regarding the R³ substituent isprovided in the sections below.

In certain embodiments, n is an integer from 1 to 6. In certainembodiments, n is 1. In certain embodiments, n is 2. In certainembodiments, n is 3. In certain embodiments, n is 4. In certainembodiments, n is 5. In certain embodiments, n is 6.

Embodiments of the R⁴ substituent are described in more detail below.

In the description of the various substituents of the chemical formulaedescribed herein, references to formula (I) are intended to includeformula (Ia) and formula (Ib) as described herein where applicable.

Formula II

In certain embodiments of formula (I), R² is sulfonyl. As such,embodiments of the presently disclosed compounds can be represented bythe following formula (II):

wherein:

R³ is selected from the group consisting of an active agent, anantioxidant, an amino acid, an amino acid derivative, a peptide, and apeptide derivative;

R⁴ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;

R⁵ is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, and substituted heteroaryl;

X¹ and X² are each independently selected from N and CH, wherein atleast one of X¹ and X² is N; and

n is an integer from 1 to 6,

or a salt or a stereoisomer thereof.

In certain embodiments, R³ is an active agent, an antioxidant, an aminoacid, an amino acid derivative, a peptide, or a peptide derivative. Incertain embodiments, R³ is an active agent. In certain embodiments, R³is an antioxidant. In certain embodiments, R³ is an amino acid. Incertain embodiments, R³ is an amino acid derivative. In certainembodiments, R³ is a peptide. In certain embodiments, R³ is a peptidederivative. Additional description regarding the R³ substituent isprovided in the sections below.

In certain embodiments, X¹ and X² are each independently selected from Nand CH, where at least one of X¹ and X² is N. In some instances, X¹ is Nand X² is N. In some instances, X¹ is N and X² is CH. In some instances,X¹ is CH and X² is N.

In certain embodiments, n is an integer from 1 to 6. In certainembodiments, n is 1. In certain embodiments, n is 2. In certainembodiments, n is 3. In certain embodiments, n is 4. In certainembodiments, n is 5. In certain embodiments, n is 6.

Embodiments of the R⁴ substituent are described in more detail below.

Embodiments of the R⁵ substituent are described in more detail below.

Formula IIa & Formula IIb

In certain embodiments, the compounds of formula (II) include compoundswhere X¹ is N and X² is N. As such, compounds of the present disclosuremay be represented by the following formula (IIa):

wherein

R³ is selected from the group consisting of an active agent, anantioxidant, an amino acid, an amino acid derivative, a peptide, and apeptide derivative;

R⁴ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; and

R⁵ is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, and substituted heteroaryl; n is aninteger from 1 to 6,

or a salt or a stereoisomer thereof.

In certain embodiments, R³ is an active agent, an antioxidant, an aminoacid, an amino acid derivative, a peptide, or a peptide derivative. Incertain embodiments, R³ is an active agent. In certain embodiments, R³is an antioxidant. In certain embodiments, R³ is an amino acid. Incertain embodiments, R³ is an amino acid derivative. In certainembodiments, R³ is a peptide. In certain embodiments, R³ is a peptidederivative. Additional description regarding the R³ substituent isprovided in the sections below.

In certain embodiments, n is an integer from 1 to 6. In certainembodiments, n is 1. In certain embodiments, n is 2. In certainembodiments, n is 3. In certain embodiments, n is 4. In certainembodiments, n is 5. In certain embodiments, n is 6.

Embodiments of the R⁴ substituent are described in more detail below.

Embodiments of the R⁵ substituent are described in more detail below.

In certain embodiments, the compounds of formula (II) include compoundswhere X¹ is N and X² is CH. As such, compounds of the present disclosuremay be represented by the following formula (IIb):

wherein

R³ is selected from the group consisting of an active agent, anantioxidant, an amino acid, an amino acid derivative, a peptide, and apeptide derivative;

R⁴ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; and

R⁵ is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, and substituted heteroaryl; n is aninteger from 1 to 6,

or a salt or a stereoisomer thereof.

In certain embodiments, R³ is an active agent, an antioxidant, an aminoacid, an amino acid derivative, a peptide, or a peptide derivative. Incertain embodiments, R³ is an active agent. In certain embodiments, R³is an antioxidant. In certain embodiments, R³ is an amino acid. Incertain embodiments, R³ is an amino acid derivative. In certainembodiments, R³ is a peptide. In certain embodiments, R³ is a peptidederivative. Additional description regarding the R³ substituent isprovided in the sections below.

In certain embodiments, n is an integer from 1 to 6. In certainembodiments, n is 1. In certain embodiments, n is 2. In certainembodiments, n is 3. In certain embodiments, n is 4. In certainembodiments, n is 5. In certain embodiments, n is 6.

Embodiments of the R⁴ substituent are described in more detail below.

Embodiments of the R⁵ substituent are described in more detail below.

In the description of the various substituents of the chemical formulaedescribed herein, references to formula (II) are intended to includeformula (IIa) and formula (IIb) as described herein where applicable.

Additional Description of the Subject Compounds

Where applicable, the description of the subject compounds in thissection applies to compounds of formulae (I), (Ia), (Ib), (II), (IIa),and (IIb).

In certain embodiments, R² is sulfonyl. For example, R² may be selectedfrom alkyl-SO₂—, substituted alkyl-SO₂—, alkenyl-SO₂—, substitutedalkenyl-SO₂—, cycloalkyl-SO₂—, substituted cycloalkyl-SO₂—,heterocycloalkyl-SO₂—, substituted heterocycloalkyl-SO₂—, aryl-SO₂—,substituted aryl-SO₂—, heteroaryl-SO₂—, and substituted heteroaryl-SO₂—.In some embodiments, R² is alkyl-SO₂— or substituted alkyl-SO₂—. In someembodiments, R² is alkenyl-SO₂— or substituted alkenyl-SO₂—. In someembodiments, R² is cycloalkyl-SO₂— or substituted cycloalkyl-SO₂—. Insome embodiments, R² is heterocycloalkyl-SO₂— or substitutedheterocycloalkyl-SO₂—. In some embodiments, R² is aryl-SO₂— orsubstituted aryl-SO₂—. In some embodiments, R² is heteroaryl-SO₂— orsubstituted heteroaryl-SO₂—.

For example, in embodiments where R² is alkyl-SO₂—, R² may be C₁₋₆alkyl-SO₂—, or C₁₋₅ alkyl-SO₂—, or C₁₋₄ alkyl-SO₂—, or C₁₋₃ alkyl-SO₂—,or C₁₋₂ alkyl-SO₂—. In some instances, R² is methyl-SO₂—. In otherembodiments, R² may be substituted alkyl-SO₂—, such as for examplesubstituted C₁₋₆ alkyl-SO₂—, or substituted C₁₋₅ alkyl-SO₂—, orsubstituted C₁₋₄ alkyl-SO₂—, or substituted C₁₋₃ alkyl-SO₂—, orsubstituted C₁₋₂ alkyl-SO₂—.

In certain embodiments, R² is aryl-SO₂— or substituted aryl-SO₂—. Forexample, in embodiments where R² is aryl-SO₂—, R² may be phenyl-SO₂—.

In other embodiments, R² is substituted aryl-SO₂—, such as for examplesubstituted phenyl-SO₂—. In certain embodiments, the substituent on thearyl group in a substituted aryl-SO₂— is C₁₋₆ alkyl, or C₁₋₅ alkyl, orC₁₋₄ alkyl, or C₁₋₃ alkyl, or C₁₋₂ alkyl. In certain embodiments, thesubstituent on the aryl group in the substituted aryl-SO₂— is methyl.For example, the substituted aryl-SO₂— may be a substituted phenyl-SO₂—,such as where the substituent on the phenyl group in the substitutedphenyl-SO₂— is C₁₋₆ alkyl, or C₁₋₅ alkyl, or C₁₋₄ alkyl, or C₁₋₃ alkyl,or C₁₋₂ alkyl. In certain embodiments, the substituent on the phenylgroup in the substituted phenyl-SO₂— is methyl. For example, R² may be2-methylphenyl-SO₂— (i.e., o-tolylsulfonyl), 3-methylphenyl-SO₂— (i.e.,m-tolylsulfonyl), or 4-methylphenyl-SO₂— (i.e., tosyl). In certainembodiments, R² is 4-methylphenyl-SO₂— (i.e., tosyl).

In certain embodiments, the substituent on the aryl group in asubstituted aryl-SO₂— is a halogen. The substituted aryl-SO₂— mayinclude one or more halogen substituents, such as 5, 4, 3, 2, or 1halogen substituents. In embodiments of the substituted aryl-SO₂— thatinclude more than one halogen substituent, each halogen substituent isindependently selected from fluoro, chloro, bromo, and iodo. In someinstances, the substituted aryl-SO₂— includes one halogen substituent.The halogen substituent may be selected from fluoro, chloro, bromo, andiodo. In some instances, the halogen substituent is fluoro. For example,the substituted aryl-SO₂— may be a substituted phenyl-SO₂—, such aswhere the substituent on the phenyl group in the substituted phenyl-SO₂—is a halogen. As described above, the substituted phenyl-SO₂— mayinclude one or more halogen substituents, such as 5, 4, 3, 2, or 1halogen substituents. In embodiments of the substituted phenyl-SO₂— thatinclude more than one halogen substituent, each halogen substituent isindependently selected from fluoro, chloro, bromo, and iodo. In someinstances, the substituted phenyl-SO₂— includes one halogen substituent.The halogen substituent may be selected from fluoro, chloro, bromo, andiodo. In some instances, the halogen substituent is fluoro. For example,R² may be 2-fluorophenyl-SO₂—, 3-fluorophenyl-SO₂—, or4-fluorophenyl-SO₂—. In certain embodiments, R² is 4-fluorophenyl-SO₂—.

In certain embodiments, R² is carboxyl (e.g., —COOH).

In certain embodiments, R² is carboxyl ester. For example, R² can becarboxyl ester represented by the group —C(O)OR⁶. In certainembodiments, R⁶ is C₁₋₆ alkyl. In certain embodiments, R⁶ is methyl. Incertain embodiments, R⁶ is ethyl. In certain embodiments, R⁶ is propyl.In certain embodiments, R⁶ is butyl. In certain embodiments, R⁶ ispentyl. In certain embodiments, R⁶ is hexyl. The C₁₋₆ alkyl may beunbranched or branched. For example, R⁶ may be propyl, such as n-propylor iso-propyl. For example, R⁶ may be butyl, such as n-butyl, sec-butyl(1-methylpropyl), iso-butyl (2-methylpropyl) or tert-butyl(1,1-dimethylethyl).

In certain embodiments, R² is aminoacyl. For example, R² may berepresented by the group —C(O)NR²¹R²², where each R²¹ and R²² isindependently selected from hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl,heteroaryl, and substituted heteroaryl, and where R²¹ and R²² areoptionally joined together with the nitrogen bound thereto to form aheterocycloalkyl, substituted heterocycloalkyl, heteroaryl, orsubstituted heteroaryl group.

In certain embodiments, R² is —C(O)NR²¹R²², where R²¹ is selected fromhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, substitutedheterocycloalkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl. In certain embodiments, R²¹ is hydrogen. In certainembodiments, R²¹ is alkyl or substituted alkyl. For example, R²¹ may bealkyl, such as C₁₋₆ alkyl, or C₁₋₅ alkyl, or C₁₋₄ alkyl, or C₁₋₃ alkyl,or C₁₋₂ alkyl. In some cases, R²¹ is methyl. In certain embodiments, R²¹is alkenyl or substituted alkenyl. In certain embodiments, R²¹ isalkynyl or substituted alkynyl. In certain embodiments, R²¹ iscycloalkyl or substituted cycloalkyl. In certain embodiments, R²¹ iscycloalkenyl or substituted cycloalkenyl. In certain embodiments, R²¹ isheterocycloalkyl or substituted heterocycloalkyl. In certainembodiments, R²¹ is aryl or substituted aryl. In certain embodiments,R²¹ is heteroaryl or substituted heteroaryl.

In certain embodiments, R² is —C(O)NR²¹R²², where R²² is selected fromhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, substitutedheterocycloalkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl. In certain embodiments, R²² is hydrogen. In certainembodiments, R²² is alkyl or substituted alkyl. For example, R²² may bealkyl, such as C₁₋₆ alkyl, or C₁₋₅ alkyl, or C₁₋₄ alkyl, or C₁₋₃ alkyl,or C₁₋₂ alkyl. In some cases, R²² is methyl. In certain embodiments, R²²is alkenyl or substituted alkenyl. In certain embodiments, R²² isalkynyl or substituted alkynyl. In certain embodiments, R²² iscycloalkyl or substituted cycloalkyl. In certain embodiments, R²² iscycloalkenyl or substituted cycloalkenyl. In certain embodiments, R²² isheterocycloalkyl or substituted heterocycloalkyl. In certainembodiments, R²² is aryl or substituted aryl. In certain embodiments,R²² is heteroaryl or substituted heteroaryl.

In certain embodiments, R²¹ and R²² are the same. For example, inembodiments where R²¹ and R²² are the same, R²¹ may be methyl and R²²may be methyl. In other embodiments, R²¹ and R²² are different.

In certain embodiments, R² is —C(O)NR²¹R²², where R²¹ and R²² are joinedtogether with the nitrogen bound thereto to form a heterocycloalkyl,substituted heterocycloalkyl, heteroaryl, or substituted heteroarylgroup. In certain embodiments, R²¹ and R²² are joined together with thenitrogen bound thereto to form a heterocycloalkyl or substitutedheterocycloalkyl. For example, R²¹ and R²² may be joined together withthe nitrogen bound thereto to form a pyrrolidinyl. In some cases, R²¹and R²² are joined together with the nitrogen bound thereto to form apyrrolidinyl, where the nitrogen of the pyrrolidinyl is attached to theadjacent —C(O)— of R² (i.e., a pyrrolidin-1-yl substituent). In certainembodiments, R²¹ and R²² are joined together with the nitrogen boundthereto to form a heteroaryl or substituted heteroaryl group.

In certain embodiments, R³ is an active agent, an antioxidant, an aminoacid, an amino acid derivative, a peptide, or a peptide derivative. Incertain embodiments, R³ is an active agent. Any number of active agentsare suitable for use, or can be modified to be rendered suitable for usein the compounds, prodrugs, conjugates and adducts described herein. Forexample, the active agent can be an active agent suitable for use in thetreatment of a disease or condition that is also amenable to treatmentusing an Nrf2 activating compound. For instance, the active agent can bean active agent suitable for use in the treatment of a disease ordisorder caused by oxidative stress (e.g., oxidative stress caused byinjury or an autoimmune or an inflammatory disease or disorder), in asubject in need of treatment. In certain instances, the active agent isan active agent suitable for use in the treatment of a disease ordisorder that is amenable to treatment by an antioxidant, such as by oneor more antioxidant proteins, peptides, peptide derivatives, aminoacids, or amino acid derivatives.

In certain instances, the active agent is an active agent suitable foruse in the treatment of a disease or disorder, where the disease ordisorder is an autoimmune or an inflammatory disease or disorder. Incertain instances, the active agent is an active agent suitable for usein the treatment of a disease or disorder, where the disease or disorderis psoriasis, such as plaque psoriasis. In certain instances, the activeagent is an active agent suitable for use in the treatment of a diseaseor disorder, where the disease or disorder is multiple sclerosis. Otherdiseases that can be treated with the active agents disclosed hereininclude pulmonary arterial hypertension (PAH), non-alcoholic andalcoholic steatohepatitis, traumatic brain injury, radiation exposureand exposure to toxic chemicals such as cyanide.

Examples of active agents suitable for use in the compounds, prodrugs,conjugates and adducts described herein include, but are not limited to,glutathione (GSH), vitamin D₃, etc. For example, glutathione may includea thiol group, where the thiol group is used to form a thioether linkagebetween glutathione and an Nrf2 activating compound to produce a prodrugas described herein. As described herein, the prodrug can undergo an invivo transformation when administered to a subject, such as a cleavagereaction, at a desired site of action such that the Nrf2 activatingcompound and the active agent (e.g., glutathione) are released at thesite of action.

In certain embodiments, R³ is an antioxidant, such as but not limited toglutathione, ascorbic acid, etc.

In certain embodiments, R³ is an amino acid or an amino acid derivative.The amino acid or amino acid derivative can include any naturallyoccurring amino acid or derivative thereof. For example, natural aminoacids include any of the commonly occurring amino acids, such as Ala orA, Cys or C, Asp or D, Glu or E, Phe or F, Gly or G, His or H, Ile or I,Lys or K, Leu or L, Met or M, Asn or N, Pro or P, Gln or Q, Arg or R,Ser or S, Thr or T, Val or V, Trp or W, Tyr or Y. In certainembodiments, the amino acid is cysteine. For example, cysteine mayinclude a thiol group, where the thiol group is used to form a thioetherlinkage between cysteine and an Nrf2 activating compound to produce aprodrug as described herein. As described herein, the prodrug canundergo an in vivo transformation when administered to a subject, suchas a cleavage reaction, at a desired site of action such that the Nrf2activating compound and the amino acid (e.g., cysteine) are released atthe site of action.

In some instances, amino acid derivatives include unnatural amino acidswith modified side chains or backbones. For example, the amino acidderivative can be a derivative of cysteine, where the natural amino acidcysteine has been modified by one or more modified groups in themolecule. In some instances, the modified cysteine derivative includesthe addition of one or more groups (such as acyl, acetyl, methyl, etc.).For example, the modified cysteine derivative may include an N-acetylgroup, and/or the carboxyl end of the cysteine residue may be modifiedto be a carboxyl ester, such as a methyl ester. Amino acid derivativesalso include amino acid analogs with the same stereochemistry as in thenaturally occurring D-form, as well as the L-form of amino acid analogs.

In certain embodiments, R³ is a peptide or a peptide derivative. Anynumber of peptides or peptide derivatives are suitable for use, or canbe modified to be rendered suitable for use in the compounds, prodrugs,conjugates and adducts described herein. For example, the peptide orpeptide derivative can be a peptide or peptide derivative suitable foruse in the treatment of a disease or condition that is also amenable totreatment using an Nrf2 activating compound. For instance, the peptideor peptide derivative can be a peptide or peptide derivative suitablefor use in the treatment of a disease or disorder caused by oxidativestress (e.g., oxidative stress caused by injury or an autoimmune or aninflammatory disease or disorder), in a subject in need of treatment. Incertain instances, the peptide or peptide derivative is a peptide orpeptide derivative suitable for use in the treatment of a disease ordisorder that is amenable to treatment by an antioxidant, such as by oneor more antioxidant peptides or peptide derivatives.

In certain embodiments, R⁴ is selected from hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl.

In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ isalkyl or substituted alkyl. In certain embodiments, R⁴ is alkyl, such asC₁₋₆ alkyl, or C₁₋₅ alkyl, or C₁₋₄ alkyl, or C₁₋₃ alkyl, or C₁₋₂ alkyl.In certain embodiments, R⁴ is methyl. In certain embodiments, R⁴ isethyl. In certain embodiments, R⁴ is substituted alkyl, such assubstituted C₁₋₆ alkyl, or substituted C₁₋₅ alkyl, or substituted C₁₋₄alkyl, or substituted C₁₋₃ alkyl, or substituted C₁₋₂ alkyl. In certainembodiments, the substituent on the alkyl group in the substituted alkylis cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, or substitutedheteroaryl. For example, the substituent on the alkyl group in thesubstituted alkyl may be cycloalkyl or substituted cycloalkyl. In someinstances, the substituent on the alkyl group in the substituted alkylis heterocyclyl or substituted heterocyclyl. In some instances, thesubstituent on the alkyl group in the substituted alkyl is aryl orsubstituted aryl. In some instances, the substituent on the alkyl groupin the substituted alkyl is heteroaryl or substituted heteroaryl.

In certain embodiments, R⁴ is substituted alkyl, such as substitutedC₁₋₆ alkyl. In certain embodiments, R⁴ is substituted methyl. In certainembodiments, R⁴ is substituted ethyl. In certain embodiments, R⁴ issubstituted propyl. In certain embodiments, R⁴ is substituted butyl. Incertain embodiments, R⁴ is substituted pentyl. In certain embodiments,R⁴ is substituted hexyl. Substituents on R⁴ include, but are not limitedto, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, hydroxyl,carboxyl, carboxyl ester, amino, substituted amino, acyl, aminoacyl,acylamino, thioalkoxy, sulfonyl, aminosulfonyl, sulfonylamino,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl. For example, R⁴ may be a substituted alkyl (e.g.,substituted C₁₋₆ alkyl), substituted with a hydroxyl. In some instances,R⁴ is a substituted alkyl (e.g., substituted C₁₋₆ alkyl), substitutedwith alkoxy or substituted alkoxy, such as a C₁₋₆ alkoxy or a C₁₋₆substituted alkoxy. In some instances, R⁴ is a substituted alkyl (e.g.,substituted C₁₋₆ alkyl), substituted with amino or substituted amino. Insome instances, R⁴ is a substituted alkyl (e.g., substituted C₁₋₆alkyl), substituted with carboxyl or carboxyl ester. In some instances,R⁴ is a substituted alkyl (e.g., substituted C₁₋₆ alkyl), substitutedwith aminoacyl or acylamino. In some instances, R⁴ is a substitutedalkyl (e.g., substituted C₁₋₆ alkyl), substituted with thioalkoxy orsulfonyl. In some instances, R⁴ is a substituted alkyl (e.g.,substituted C₁₋₆ alkyl), substituted with cycloalkyl or substitutedcycloalkyl, such as, for example, C₃₋₈ cycloalkyl or C₃₋₈ substitutedcycloalkyl, or C₃₋₆ cycloalkyl or C₃₋₆ substituted cycloalkyl, or C₃₋₅cycloalkyl or C₃₋₅ substituted cycloalkyl, or C₃₋₄ cycloalkyl or C₃₋₄substituted cycloalkyl. In some instances, R⁴ is a substituted alkyl(e.g., substituted C₁₋₆ alkyl), substituted with heterocyclyl orsubstituted heterocyclyl, such as, for example, C₃₋₈ heterocyclyl orC₃₋₈ substituted heterocyclyl, or C₃₋₆ heterocyclyl or C₃₋₆ substitutedheterocyclyl, or C₃₋₅ heterocyclyl or C₃₋₅ substituted heterocyclyl, orC₃₋₄ heterocyclyl or C₃₋₄ substituted heterocyclyl. In some instances,R⁴ is a substituted alkyl (e.g., substituted C₁₋₆ alkyl), substitutedwith aryl or substituted aryl, such as, for example, C₃₋₆ aryl or C₃₋₆substituted aryl, such as phenyl or substituted phenyl. In someinstances, R⁴ is a substituted alkyl (e.g., substituted C₁₋₆ alkyl),substituted with heteroaryl or substituted heteroaryl, such as, forexample, C₃₋₆ heteroaryl or C₃₋₆ substituted heteroaryl, such as pyridylor substituted pyridyl (e.g., 3-pyridyl or substituted 3-pyridyl).Combinations of the above substituents on R⁴ are also included. Any ofthe R⁴ groups described herein may be included in the compounds of thepresent disclosure.

For example, the substituted alkyl may be a substituted methyl group,where the substituent on the methyl group is cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, or substituted heteroaryl. In some instances, thesubstituent on the methyl group is cycloalkyl or substituted cycloalkyl.In some instances, the substituent on the methyl group is heterocyclylor substituted heterocyclyl. In some instances, the substituent on themethyl group is aryl or substituted aryl. For example, the substituenton the methyl group may be an aryl, such as phenyl (i.e., R⁴ is benzyl).In some instances, the substituent on the methyl group is heteroaryl orsubstituted heteroaryl, such as pyridyl or substituted pyridyl (e.g.,3-pyridyl or substituted 3-pyridyl).

In certain embodiments, R⁴ is alkenyl or substituted alkenyl. In certainembodiments, R⁴ is alkynyl or substituted alkynyl.

In certain embodiments, R⁴ is cycloalkyl or substituted cycloalkyl. Incertain embodiments, R⁴ is cyclohexyl or substituted cyclohexyl. Incertain embodiments, R⁴ is cyclopentyl or substituted cyclopentyl. Incertain embodiments, R⁴ is cyclobutyl or substituted cyclobutyl. Incertain embodiments, R⁴ is cyclopropyl or substituted cyclopropyl. Incertain embodiments, R⁴ is heterocyclyl or substituted heterocyclyl. Incertain embodiments, R⁴ is 4-tetrahydropyranyl or substituted4-tetrahydropyranyl.

In certain embodiments, R⁴ is aryl or substituted aryl. In certainembodiments, R⁴ is phenyl or substituted phenyl. In certain embodiments,R⁴ is phenyl. In certain embodiments, R⁴ is substituted phenyl. Incertain embodiments, R⁴ is heteroaryl or substituted heteroaryl. Incertain embodiments, R⁴ is heteroaryl. In certain embodiments, R⁴ issubstituted heteroaryl. In certain embodiments, R⁴ is pyridyl orsubstituted pyridyl. In certain embodiments, R⁴ is 2-pyridyl, 3-pyridylor 4-pyridyl. In certain embodiments, R⁴ is 3-pyridyl. In certainembodiments, R⁴ is substituted 2-pyridyl, substituted 3-pyridyl orsubstituted 4-pyridyl.

In certain embodiments, R⁵ is alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, or substituted heteroaryl. In someembodiments, R⁵ is alkyl or substituted alkyl. In some embodiments, R⁵is alkenyl or substituted alkenyl. In some embodiments, R⁵ is cycloalkylor substituted cycloalkyl. In some embodiments, R⁵ is heterocycloalkylor substituted heterocycloalkyl. In some embodiments, R⁵ is aryl orsubstituted aryl. In some embodiments, R⁵ is heteroaryl or substitutedheteroaryl.

For example, in embodiments where R⁵ is alkyl, R⁵ may be C₁₋₆ alkyl, orC₁₋₅ alkyl, or C₁₋₄ alkyl, or C₁₋₃ alkyl, or C₁₋₂ alkyl. In someinstances, R⁵ is methyl. In other embodiments, R⁵ may be substitutedalkyl, such as for example substituted C₁₋₆ alkyl, or substituted C₁₋₅alkyl, or substituted C₁₋₄ alkyl, or substituted C₁₋₃ alkyl, orsubstituted C₁₋₂ alkyl.

In certain embodiments, R⁵ is aryl or substituted aryl. For example, inembodiments where R⁵ is aryl, R⁵ may be phenyl.

In other embodiments, R⁵ is substituted aryl, such as for examplesubstituted phenyl. In certain embodiments, the substituent on the arylgroup in a substituted aryl is C₁₋₆ alkyl, or C₁-5 alkyl, or C₁₋₄ alkyl,or C₁₋₃ alkyl, or C₁₋₂ alkyl. In certain embodiments, the substituent onthe aryl group in the substituted aryl is methyl. For example, thesubstituted aryl may be a substituted phenyl, such as where thesubstituent on the phenyl group in the substituted phenyl is C₁₋₆ alkyl,or C₁₋₅ alkyl, or C₁₋₄ alkyl, or C₁₋₃ alkyl, or C₁₋₂ alkyl. In certainembodiments, the substituent on the phenyl group in the substitutedphenyl is methyl. For example, R⁵ may be 2-methylphenyl, 3-methylphenyl,or 4-methylphenyl. In certain embodiments, R⁵ is 4-methylphenyl.

In certain embodiments, the substituent on the aryl group in asubstituted aryl is a halogen. The substituted aryl may include one ormore halogen substituents, such as 5, 4, 3, 2, or 1 halogensubstituents. In embodiments of the substituted aryl that include morethan one halogen substituent, each halogen substituent is independentlyselected from fluoro, chloro, bromo, and iodo. In some instances, thesubstituted aryl includes one halogen substituent. The halogensubstituent may be selected from fluoro, chloro, bromo, and iodo. Insome instances, the halogen substituent is fluoro. For example, thesubstituted aryl may be a substituted phenyl, such as where thesubstituent on the phenyl group in the substituted phenyl is a halogen.As described above, the substituted phenyl may include one or morehalogen substituents, such as 5, 4, 3, 2, or 1 halogen substituents. Inembodiments of the substituted phenyl that include more than one halogensubstituent, each halogen substituent is independently selected fromfluoro, chloro, bromo, and iodo. In some instances, the substitutedphenyl includes one halogen substituent. The halogen substituent may beselected from fluoro, chloro, bromo, and iodo. In some instances, thehalogen substituent is fluoro. For example, R⁵ may be 2-fluorophenyl,3-fluorophenyl, or 4-fluorophenyl. In certain embodiments, R⁵ is4-fluorophenyl.

Particular compounds disclosed herein, and salts or solvates orstereoisomers thereof, include:

-   Compound 1:    N⁵-((2R)-1-((carboxymethyl)amino)-3-((1-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-2-tosylethyl)thio)-1-oxopropan-2-yl)-L-glutamine;-   Compound 2:    N⁵-((2R)-1-((carboxymethyl)amino)-3-((3-methoxy-3-oxo-1-(5-oxo-4-(pyridin-3-yl)-4,5-dihydro-1H-tetrazol-1-yl)propyl)thio)-1-oxopropan-2-yl)-L-glutamine;-   Compound 3: methyl    N-acetyl-S-(1-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(phenylsulfonyl)ethyl)-L-cysteinate;-   Compound 4:    N-acetyl-S-(1-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(phenylsulfonyl)ethyl)-L-cysteine;-   Compound 5:    (2R)-2-amino-3-(1-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(phenylsulfonyl)ethylthio)propanoic    acid;-   Compound 6:    (2S)-2-amino-5-((2R)-1-(carboxymethylamino)-3-(1-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(phenylsulfonyl)ethylthio)-1-oxopropan-2-ylamino)-5-oxopentanoic    acid;-   Compound 7:    2-acetamido-4-(1-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(phenylsulfonyl)ethylthio)butanoic    acid;-   Compound 8:    (2R)-2-acetamido-3-(1-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(phenylsulfonyl)ethylthio)propanamide;-   Compound 9: methyl    N-acetyl-S-(3-methoxy-3-oxo-1-(5-oxo-4-(pyridin-3-yl)-4,5-dihydro-1H-tetrazol-1-yl)propyl)-L-cysteinate;    and-   Compound 10: methyl    N-acetyl-S-(1-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-2-tosylethyl)-L-cysteinate.

In certain embodiments, the compound has the structure:

In certain embodiments, the compound has the structure:

In certain embodiments, the compound has the structure:

In certain embodiments, the compound has the structure:

In certain embodiments, the compound has the structure:

In certain embodiments, the compound has the structure:

In certain embodiments, the compound has the structure:

In certain embodiments, the compound has the structure:

In certain embodiments, the compound has the structure:

In certain embodiments, the compound has the structure:

In certain embodiments, the prodrug is compound that is a conjugate ofdimethylfumarate (DMF) and glutathione (GSH). For instance, glutathionemay include a thiol group, where the thiol group is used to form athioether linkage between glutathione and dimethylfumarate to produce aprodrug as described herein. As described herein, the prodrug canundergo an in vivo transformation when administered to a subject, suchas a cleavage reaction, at a desired site of action such thatglutathione and dimethylfumarate are released at the site of action. Forexample, the prodrug may be a compound having the structure:

N⁵-((2R)-1-((carboxymethyl)amino)-3-((1,4-dimethoxy-1,4-dioxobutan-2-yl)thio)-1-oxopropan-2-yl)-L-glutamine(Compound 11)

In certain embodiments, the prodrug is compound that is a conjugate ofdimethylfumarate and a thiol-containing compound. For instance, thethiol-containing compound may include a thiol group, where the thiolgroup is used to form a thioether linkage between the thiol-containingcompound and dimethylfumarate to produce a prodrug as described herein.As described herein, the prodrug can undergo an in vivo transformationwhen administered to a subject, such as a cleavage reaction, at adesired site of action such that dimethylfumarate and thethiol-containing compound are released at the site of action. Forexample, the prodrug may be a compound having the structure:

dimethyl2-(((R)-2-(acetyl-λ²-azaneyl)-3-methoxy-3-oxopropyl)thio)succinate(Compound 12)

The prodrugs, compounds, conjugates and adducts described herein can beisolated by procedures known to those skilled in the art. The prodrugs,compounds, conjugates and adducts described herein may be obtained, forinstance, by a resolution technique or by chromatography techniques(e.g., silica gel chromatography, chiral chromatography, etc.). As usedherein, the term “isolated” refers to compounds that are non-naturallyoccurring and can be obtained or purified from synthetic reactionmixtures. Isolated compounds may find use in the pharmaceuticalcompositions and methods of treatment described herein.

The compounds described also include isotopically labeled compoundswhere one or more atoms have an atomic mass different from the atomicmass conventionally found in nature. Examples of isotopes that may beincorporated into the compounds disclosed herein include, but are notlimited to, ²H, ³H, 11C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, etc. Thus, thedisclosed compounds may be enriched in one or more of these isotopesrelative to the natural abundance of such isotope. By way of example,deuterium (²H; D) has a natural abundance of about 0.015%. Accordingly,for approximately every 6,500 hydrogen atoms occurring in nature, thereis one deuterium atom. Specifically contemplated herein are compoundsenriched in deuterium at one or more positions. Thus, deuteriumcontaining compounds of the disclosure have deuterium at one or morepositions (as the case may be) in an abundance of greater than 0.015%.In some embodiments, one or more (e.g., 1, 2, 3, 4, 5, 6, 7 or more)hydrogen atoms of an R¹ group of any one of the subject compoundsdescribed herein are substituted with a deuterium.

Pharmaceutical Compositions

In certain embodiments, the disclosed compounds are useful for thetreatment of a disease or disorder, such as an autoimmune or aninflammatory disease or disorder. Accordingly, pharmaceuticalcompositions comprising at least one disclosed compound are alsodescribed herein. For example, the present disclosure providespharmaceutical compositions that include a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent disclosure or a pharmaceutically acceptable salt or solvate orstereoisomer thereof.

A pharmaceutical composition that includes a subject compound may beadministered to a patient alone, or in combination with othersupplementary active agents. For example, one or more compoundsaccording to the present disclosure can be administered to a patientwith or without supplementary active agents. The pharmaceuticalcompositions may be manufactured using any of a variety of processes,including, but not limited to, conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping, lyophilizing, and the like. The pharmaceutical compositioncan take any of a variety of forms including, but not limited to, asterile solution, suspension, emulsion, spray dried dispersion,lyophilisate, tablet, microtablets, pill, pellet, capsule, powder,syrup, elixir or any other dosage form suitable for administration.

A subject compound may be administered to a subject using any convenientmeans capable of resulting in the desired reduction in disease conditionor symptom. Thus, a subject compound can be incorporated into a varietyof formulations for therapeutic administration. More particularly, asubject compound can be formulated into pharmaceutical compositions bycombination with appropriate pharmaceutically acceptable carriers ordiluents, and may be formulated into preparations in solid, semi-solid,liquid or gaseous forms, such as tablets, capsules, powders, granules,ointments, solutions, suppositories, injections, inhalants, aerosols,and the like.

Formulations for pharmaceutical compositions are described in, forexample, Remington's Pharmaceutical Sciences, by E. W. Martin, MackPublishing Co., Easton, Pa., 19th Edition, 1995, which describesexamples of formulations (and components thereof) suitable forpharmaceutical delivery of disclosed compounds. Pharmaceuticalcompositions that include at least one of the subject compounds can beformulated for use in human or veterinary medicine. Particularformulations of a disclosed pharmaceutical composition may depend, forexample, on the mode of administration and/or on the location of thesubject to be treated. In some embodiments, formulations include apharmaceutically acceptable carrier in addition to at least one activeingredient, such as a subject compound. In other embodiments, othermedicinal or pharmaceutical agents, for example, with similar, relatedor complementary effects on the disease or condition being treated canalso be included as active ingredients in a pharmaceutical composition.

Pharmaceutically acceptable carriers useful for the disclosed methodsand compositions may depend on the particular mode of administrationbeing employed. For example, parenteral formulations may includeinjectable fluids, such as, but not limited to, pharmaceutically andphysiologically acceptable fluids such as water, physiological saline,balanced salt solutions, aqueous dextrose, glycerol or the like as avehicle. For solid compositions (e.g., powder, pill, tablet, or capsuleforms), non-toxic solid carriers can include, for example,pharmaceutical grades of mannitol, lactose, starch, or magnesiumstearate. In addition to biologically neutral carriers, pharmaceuticalcompositions to be administered can optionally contain minor amounts ofnon-toxic auxiliary substances (e.g., excipients), such as wetting oremulsifying agents, preservatives, and pH buffering agents and the like;for example, sodium acetate or sorbitan monolaurate. Other examples ofexcipients include, nonionic solubilizers, such as cremophor, orproteins, such as human serum albumin or plasma preparations.

Some examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) water (e.g., pyrogen-free water); (17) isotonic saline; (18)Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

The disclosed pharmaceutical compositions may be formulated as apharmaceutically acceptable salt of a disclosed compound. Examples ofpharmaceutically acceptable salts include non-toxic salts of a free baseform of a compound that possesses the desired pharmacological activityof the free base. These salts may be derived from inorganic or organicacids. Non-limiting examples of suitable inorganic acids arehydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid,hydroiodic acid, and phosphoric acid. Non-limiting examples of suitableorganic acids are acetic acid, propionic acid, glycolic acid, lacticacid, pyruvic acid, malonic acid, succinic acid, malic acid, maleicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, methylsulfonic acid, salicylic acid, formic acid, trichloroacetic acid,trifluoroacetic acid, gluconic acid, asparagic acid, aspartic acid,benzenesulfonic acid, para-toluenesulfonic acid, naphthalenesulfonicacid, combinations thereof, and the like. In certain embodiments, thepharmaceutically acceptable salt includes formic acid. Other examples ofpharmaceutically acceptable salts include non-toxic salts of a free acidform of compounds according to the present disclosure. Such salts arederived from inorganic or organic bases. Pharmaceutically acceptablebase addition salts include those derived from inorganic bases such assodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc,copper, manganese, aluminum salts, combinations thereof, and the like.Examples of salts are the ammonium, potassium, sodium, calcium, andmagnesium salts. Salts of the presently disclosed compounds can bederived from pharmaceutically acceptable organic non-toxic basesincluding, but not limited to, salts of primary, secondary, and tertiaryamines, substituted amines including naturally occurring substitutedamines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, 2-amino-2-hydroxymethyl-propane-1,3-diol (“Tris”salt), dicyclohexylamine, lysine, arginine, histidine, caffeine,procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, combinations thereof, and the like. Pharmaceuticallyacceptable salts are described further in S. M. Berge, et al.,“Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:1-19 and Remington'sPharmaceutical Sciences, 19th Edition, Mack Publishing Company, Easton,Pa., 1995.

A subject compound can be used alone or in combination with appropriateadditives to make tablets, powders, granules or capsules, for example,with conventional additives, such as lactose, mannitol, corn starch orpotato starch; with binders, such as crystalline cellulose, cellulosederivatives, acacia, corn starch or gelatins; with disintegrators, suchas corn starch, potato starch or sodium carboxymethylcellulose; withlubricants, such as talc or magnesium stearate; and if desired, withdiluents, buffering agents, moistening agents, preservatives andflavoring agents. Such preparations can be used for oral administration.

A subject compound can be formulated into preparations for injection bydissolving, suspending or emulsifying the compound in an aqueous ornonaqueous solvent, such as vegetable or other similar oils, syntheticaliphatic acid glycerides, esters of higher aliphatic acids or propyleneglycol; and if desired, with conventional additives such assolubilizers, isotonic agents, suspending agents, emulsifying agents,stabilizers and preservatives. The preparation may also be emulsified orthe active ingredient encapsulated in liposome vehicles. Formulationssuitable for injection can be administered by an intravitreal,intraocular, intramuscular, subcutaneous, sublingual, or other route ofadministration, e.g., injection into the gum tissue or other oraltissue. Such formulations are also suitable for topical administration.

In some embodiments, a subject compound can be delivered by a continuousdelivery system. The term “continuous delivery system” is usedinterchangeably herein with “controlled delivery system” and encompassescontinuous (e.g., controlled) delivery devices (e.g., pumps) incombination with catheters, injection devices, and the like, a widevariety of which are known in the art.

A subject compound can be utilized in aerosol formulation to beadministered via inhalation. A subject compound can be formulated intopressurized acceptable propellants such as dichlorodifluoromethane,propane, nitrogen and the like.

Furthermore, a subject compound can be made into suppositories by mixingwith a variety of bases such as emulsifying bases or water-solublebases. A subject compound can be administered rectally via asuppository. The suppository can include vehicles such as cocoa butter,carbowaxes and polyethylene glycols, which melt at body temperature, yetare substantially solid at room temperature.

The term “unit dosage form,” as used herein, refers to physicallydiscrete units suitable as unitary dosages for human and animalsubjects, each unit containing a predetermined quantity of a subjectcompound calculated in an amount sufficient to produce the desiredeffect in association with a pharmaceutically acceptable diluent,carrier or vehicle. The specifications for a subject compound depend onthe particular compound employed and the effect to be achieved, and thepharmacodynamics associated with each compound in the host.

The dosage form of a disclosed pharmaceutical composition may bedetermined by the mode of administration chosen. For example, inaddition to injectable fluids, topical or oral dosage forms may beemployed. Topical preparations may include eye drops, ointments, spraysand the like. Oral formulations may be liquid (e.g., syrups, solutionsor suspensions), or solid (e.g., powders, pills, tablets, or capsules).Methods of preparing such dosage forms are known, or will be apparent,to those skilled in the art.

Certain embodiments of the pharmaceutical compositions that include asubject compound may be formulated in unit dosage form suitable forindividual administration of precise dosages. The amount of activeingredient administered may depend on the subject being treated, theseverity of the affliction, and the manner of administration, and isknown to those skilled in the art. In certain instances, the formulationto be administered contains a quantity of the compounds disclosed hereinin an amount effective to achieve the desired effect in the subjectbeing treated.

Each therapeutic compound can independently be in any dosage form, suchas those described herein, and can also be administered in various ways,as described herein. For example, the compounds may be formulatedtogether, in a single dosage unit (that is, combined together in oneform such as capsule, tablet, powder, or liquid, etc.) as a combinationproduct. Alternatively, when not formulated together in a single dosageunit, an individual subject compound may be administered at the sametime as another therapeutic compound or sequentially, in any orderthereof.

A disclosed compound can be administered alone, as the sole activepharmaceutical agent, or in combination with one or more additionalcompounds of the present disclosure or in conjunction with other agents.When administered as a combination, the therapeutic agents can beformulated as separate compositions that are administered simultaneouslyor at different times, or the therapeutic agents can be administeredtogether as a single composition combining two or more therapeuticagents. Thus, the pharmaceutical compositions disclosed hereincontaining a compound of the present disclosure optionally include othertherapeutic agents. Accordingly, certain embodiments are directed tosuch pharmaceutical compositions, where the composition further includesa therapeutically effective amount of an agent selected as is known tothose of skill in the art.

Methods of Administration

The subject compounds find use for treating a disease or disorder in asubject, such as an autoimmune or an inflammatory disease or disorder.The route of administration may be selected according to a variety offactors including, but not limited to, the condition to be treated, theformulation and/or device used, the patient to be treated, and the like.Routes of administration useful in the disclosed methods include but arenot limited to oral and parenteral routes, such as intravenous (iv),intraperitoneal (ip), rectal, topical, ophthalmic, nasal, andtransdermal. Formulations for these dosage forms are described herein.

An effective amount of a subject compound may depend, at least, on theparticular method of use, the subject being treated, the severity of theaffliction, and the manner of administration of the therapeuticcomposition. A “therapeutically effective amount” of a composition is aquantity of a specified compound sufficient to achieve a desired effectin a subject (e.g., patient) being treated. For example, this may be theamount of a subject compound necessary to prevent, inhibit, reduce orrelieve a disease or disorder in a subject, such as an autoimmune or aninflammatory disease or disorder. Ideally, a therapeutically effectiveamount of a compound is an amount sufficient to prevent, inhibit, reduceor relieve a disease or disorder in a subject without causing asubstantial cytotoxic effect on host cells in the subject.

Therapeutically effective doses of a subject compound or pharmaceuticalcomposition can be determined by one of skill in the art, with a goal ofachieving local (e.g., tissue) concentrations that are at least as highas the EC₅₀ of an applicable compound disclosed herein.

An example of a dosage range is from 0.1 to 200 mg/kg body weight orallyin single or divided doses. In some embodiments, a dosage range is from1.0 to 100 mg/kg body weight orally in single or divided doses,including from 1.0 to 50 mg/kg body weight, from 1.0 to 25 mg/kg bodyweight, from 1.0 to 10 mg/kg body weight (assuming an average bodyweight of approximately 70 kg; values may be adjusted accordingly forpersons weighing more or less than average). For oral administration,the compositions are, for example, provided in the form of a tabletcontaining from about 10 to about 1000 mg of the active ingredient, suchas 25 to 750 mg, or 50 to 500 mg, for example 75 mg, 100 mg, 200 mg, 250mg, 400 mg, 500 mg, 600 mg, 750 mg, or 1000 mg of the active ingredientfor the symptomatic adjustment of the dosage to the subject beingtreated. In certain embodiments of an oral dosage regimen, a tabletcontaining from 500 mg to 1000 mg active ingredient is administered once(e.g., a loading dose) followed by administration of ½ (i.e., half)dosage tablets (e.g., from 250 to 500 mg) each 6 to 24 hours for 3 daysor more.

The specific dose level and frequency of dosage for any particularsubject may be varied and may depend upon a variety of factors,including the activity of the subject compound, the metabolic stabilityand length of action of that compound, the age, body weight, generalhealth, sex and diet of the subject, mode and time of administration,rate of excretion, drug combination, and severity of the condition ofthe host undergoing therapy.

Embodiments of the present disclosure also include combinations of oneor more disclosed compounds with one or more other agents or therapiesuseful in the treatment of a disease or disorder. In certain instances,the disease or disorder is an autoimmune or an inflammatory disease ordisorder. In certain instances, the disease or disorder is psoriasis,such as plaque psoriasis. In certain instances, the disease or disorderis multiple sclerosis. For example, one or more disclosed compounds maybe administered in combination with therapeutically effective doses ofother medicinal and pharmaceutical agents, or in combination othernon-medicinal therapies, such as hormone (e.g., corticosteroids) orradiation therapy (e.g., phototherapy). The term “administration incombination with” refers to both concurrent and sequentialadministration of the active agents.

Methods of Treatment

The compounds described in the present disclosure are useful fortreating a disease or disorder, such as a disease or disorder caused byoxidative stress (e.g., oxidative stress caused by injury or anautoimmune or an inflammatory disease or disorder), in a subject in needof treatment. In certain instances, the disease or disorder is one thatis amenable to treatment by an antioxidant, such as by one or moreantioxidant proteins. In certain instances, the disease or disorder isone that is amenable to treatment by an increase in expression ofantioxidant protein(s) in a subject in need of treatment. In certaininstances, the disease or disorder is one that is amenable to treatmentby an increase in expression of antioxidant protein(s), where theexpression of the antioxidant protein(s) is regulated by Nrf2, in asubject in need of treatment.

In certain instances, the disease or disorder is an autoimmune or aninflammatory disease or disorder. In certain instances, the disease ordisorder is psoriasis, such as plaque psoriasis. In certain instances,the disease or disorder is multiple sclerosis. Other diseases that canbe treated with the compounds disclosed herein include pulmonaryarterial hypertension (PAH), non-alcoholic and alcoholicsteatohepatitis, traumatic brain injury, radiation exposure and exposureto toxic chemicals such as cyanide.

Accordingly, the present disclosure provides methods of treating aninflammatory disease in a subject by administering an effective amountof a subject compound, including a salt or solvate or stereoisomerthereof, so as to treat inflammation. For example, the presentdisclosure provides a method of treating an inflammatory disease in asubject. In certain embodiments, the method includes administering tothe subject (e.g., patient) a compound of the present disclosure, or asalt or solvate or stereoisomer thereof.

In addition, the present disclosure also provides methods of treating anautoimmune disease in a subject by administering to the subject aneffective amount of a subject compound, including a salt or solvate orstereoisomer thereof, so as to treat the autoimmune disease. Forexample, the present disclosure also provides a method of treating anautoimmune disease in a subject. In certain embodiments, the methodincludes administering to the subject (e.g., patient) a compound of thepresent disclosure, or a salt or solvate or stereoisomer thereof.

In certain embodiments, compounds useful in the methods of treatmentdisclosed herein (e.g., for treating an autoimmune or inflammatorydisease or disorder) include compounds of formula (I), (Ia), (Ib), (II),(IIa), and (IIb), as disclosed herein.

In certain embodiments, the compound useful in the methods of treatmentdisclosed herein (e.g., for treating an autoimmune or inflammatorydisease or disorder) is a compound of the following structure:

In certain embodiments, the compound useful in the methods of treatmentdisclosed herein (e.g., for treating an autoimmune or inflammatorydisease or disorder) is a compound of the following structure:

In certain embodiments, the compound useful in the methods of treatmentdisclosed herein (e.g., for treating an autoimmune or inflammatorydisease or disorder) is a compound of the following structure:

In certain embodiments, the compound useful in the methods of treatmentdisclosed herein (e.g., for treating an autoimmune or inflammatorydisease or disorder) is a compound of the following structure:

In certain embodiments, the compound useful in the methods of treatmentdisclosed herein (e.g., for treating an autoimmune or inflammatorydisease or disorder) is a compound of the following structure:

In certain embodiments, the compound useful in the methods of treatmentdisclosed herein (e.g., for treating an autoimmune or inflammatorydisease or disorder) is a compound of the following structure:

In certain embodiments, the compound useful in the methods of treatmentdisclosed herein (e.g., for treating an autoimmune or inflammatorydisease or disorder) is a compound of the following structure:

In certain embodiments, the compound useful in the methods of treatmentdisclosed herein (e.g., for treating an autoimmune or inflammatorydisease or disorder) is a compound of the following structure:

In certain embodiments, the compound useful in the methods of treatmentdisclosed herein (e.g., for treating an autoimmune or inflammatorydisease or disorder) is a compound of the following structure:

In certain embodiments, the compound useful in the methods of treatmentdisclosed herein (e.g., for treating an autoimmune or inflammatorydisease or disorder) is a compound of the following structure:

In certain embodiments, the compound useful in the methods of treatmentdisclosed herein (e.g., for treating an autoimmune or inflammatorydisease or disorder) is a compound of the following structure:

In certain embodiments, the compound useful in the methods of treatmentdisclosed herein (e.g., for treating an autoimmune or inflammatorydisease or disorder) is a compound of the following structure:

Diseases or conditions for treatment according to the present disclosureinclude, but are not limited to, psoriasis, multiple sclerosis,inflammatory bowel disease, asthma, chronic obstructive pulmonarydisease, and arthritis. For example, diseases or conditions fortreatment according to the present disclosure include, but are notlimited to, immunological, autoimmune, and/or inflammatory diseasesincluding: psoriasis such as plaque psoriasis; asthma; chronicobstructive pulmonary diseases (COPD) such as bronchitis, emphysema, aswell as other lung disorders such as asbestosis, pneumoconiosis, andpulmonary neoplasms; arthritis such as inflammatory arthritis, includingrheumatoid arthritis, juvenile rheumatoid arthritis (juvenile idiopathicarthritis), psoriatic arthritis, and ankylosing spondylitis producejoint inflammation; cardiac insufficiency including left ventricularinsufficiency, myocardial infarction and angina pectoris; mitochondrialand neurodegenerative diseases such as Parkinson's disease, Alzheimer'sdisease, Huntington's disease, amyotrophic lateral sclerosis (ALS or LouGehrig's Disease), retinopathia pigmentosa and mitochondrialencephalomyopathy; transplantation rejection; autoimmune diseasesincluding multiple sclerosis, ischemia and reperfusion injury,AGE-induced genome damage; inflammatory bowel diseases (IBD) such asCrohn's disease and ulcerative colitis; and NF-κB mediated diseases.

Further diseases or conditions for treatment according to the presentdisclosure include, but are not limited to, rheumatica, granulomaannulare, lupus, autoimmune carditis, eczema, sarcoidosis, andautoimmune diseases including acute disseminated encephalomyelitis,Addison's disease, alopecia areata, ankylosing spondylitis,antiphospholipid antibody syndrome, autoimmune hemolytic anemia,autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid,Behcet's disease, celiac disease, Chagas disease, chronic obstructivepulmonary disease, Crohn's disease, dermatomyositis, diabetes mellitustype I, endometriosis, Goodpasture's syndrome, Graves' disease,Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativea,Kawasaki disease, IgA neuropathy, idiopathic thrombocytopenic purpura,interstitial cystitis, lupus erythematosus, mixed connective tissuedisease, morphea, multiple sclerosis, myasthenia gravis, narcolepsy,neuromyotonia, pemphigus vulgaris, pernicious anaemia, psoriasis,psonatic arthritis, polymyositis, primary biliary cirrhosis, rheumatoidarthritis, schizophrenia, scleroderma, Sjogren's syndrome, stiff personsyndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo,and Wegener's granulomatosis.

Additional diseases or conditions for treatment according to the presentdisclosure include, but are not limited to, necrobiosis lipodica,granuloma annulare, sarcoidosis, alopecia areata, cheilitisgranulomatosa, recurrent oral aphthae, non-infectious chronic uveitis,pityriasis rubra pilaris, annular elastolytic giant cell granuloma, andthe like. Diseases or conditions for treatment according to the presentdisclosure also include Huntington's disease, malaria, HIV,HIV-associated neurodegenerative disorders, bronchial asthma, myocardialinfarction, chronic obstructive pulmonary disease, HSV1 keratitis, andimmunosuppression due to organ transplantation.

In certain embodiments, the subject compounds are useful for treating adisease or disorder, such as cell proliferative disorders. Cellproliferative disorders treatable with the subject compound disclosedherein relate to any disorder characterized by aberrant cellproliferation. These include various tumors and cancers, benign ormalignant, metastatic or non-metastatic. Specific properties of cancers,such as tissue invasiveness or metastasis, can be targeted using themethods described herein. Cell proliferative disorders include a varietyof cancers, including, among others, breast cancer, colon cancer,melanoma, glioblastoma, ovarian cancer, renal cancer, gastrointestinalcancer, kidney cancer, bladder cancer, pancreatic cancer, lung squamouscarcinoma, and adenocarcinoma.

Compounds of the present disclosure may also find use as research tools.Accordingly, the present disclosure also provides for a method for usinga compound of the present disclosure or a salt or solvate orstereoisomer thereof as a research tool for studying a biological systemor sample, or for discovering new chemical compounds having use fortreating a an autoimmune or an inflammatory disease or disorder in asubject.

Embodiments are also directed to a compound of the present disclosure ora salt or solvate or stereoisomer thereof, for use in therapy or as amedicament. For instance, embodiments include the use of a compound ofthe present disclosure or a salt or solvate or stereoisomer thereof, forthe manufacture of a medicament; for example, for the manufacture of amedicament for the treatment of an autoimmune or inflammatory disease ordisorder. In some cases, the embodiments are also directed to the use ofa compound of the present disclosure or a salt or solvate orstereoisomer thereof for the manufacture of a medicament for thetreatment of an autoimmune disease, such as multiple sclerosis. Theembodiments are also directed to the use of a compound of the presentdisclosure or a salt or solvate or stereoisomer thereof for themanufacture of a medicament for the treatment of an inflammatory diseaseor disorder, such as psoriasis. Further diseases or conditions fortreatment according to the present disclosure are discussed above.

Characterization of Functional Properties

The following are examples of assays useful in characterizing activitiesof a compound of the present disclosure.

A. In Vitro

1. Glutathione Depletion Assay

In one aspect the present compounds exert their therapeutic effects byacting as a Michael acceptor for reactive thiol groups in vivo. See, forexample, Lehmann et al. Dimethylfumarate Induces Immunosuppression viaGlutathione Depletion and Subsequent Induction of Heme Oxygenase 1,Journal of Investigative Dermatology (2007) 127, 835-845. Accordingly,the present compounds may be assessed in vitro by reaction withglutathione as follows:

A mixture of dimethylfumarate (5.2 mg, 3.6 mmol) and reduced glutathione(22.4 mg, 7.3 mmol; 2 equiv.) in d₆-DMSO (1.2 mL) were combined in ascrew-top vial and the mixture was stirred at 35° C. (with the topsecurely fastened). Aliquots of sample were removed at intermittent timepoints and a ¹H NMR taken [note: after analysis by ¹H NMR, the samplecan be returned to the heated vial and reaction continued). ¹H NMRindicates majority reaction with glutathione (by Michael addition to thedouble bond) after 3 hr, and complete reaction by 27 hr.

The above reaction was repeated using monomethylfumarate (11.4 mg, 8.8mmol) and reduced glutathione (55.5 mg, 18.0 mmol) in d₆-DMSO (3.0 mL)at 35° C. As judged by ¹H NMR, majority reaction was observed by 27 hr.

The above reaction was repeated using methyl(E)-3-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)acrylate (6.2 mg, 3.6 mmol)and reduced glutathione (22.4 mg, 7.2 mmol) in d₆-DMSO (1.2 mL) at 35°C. As judged by ¹H NMR, majority reaction was observed by 30 hr.

The above reaction was repeated using methyl(E)-3-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)acrylate (6.6 mg, 3.6mmol) and reduced glutathione (22.4 mg, 7.2 mmol) in d₆-DMSO (1.2 mL) at35° C. As judged by ¹H NMR, majority reaction was observed by 30 hr.

In all the above cases, dis-appearance of the alkene proton signals fromthe starting material are used to determine the extent of Michaelreaction with glutathione.

As would be understood by those of skill in the art, the aboveexperiments can be repeated by varying the equivalents of reducedglutathione (0.5 to 2 equivalents); the reactions can also be run in amixture of d₆-DMSO and D₂O; and the temperature of the reaction can alsobe varied from room temperature to 35° C. (35° C. being used to mimicbody temperature). As used herein “majority reaction” means a greaterthan 50% reduction in alkene proton signal as observed by ¹H NMR.

Other in vitro assays well known to those of skill in the art can beused to demonstrate the anti-inflammatory efficacy of the presentcompounds. For example, certain compounds blocked production of theinflammatory cytokine IL-23 in THP1 cells stimulated with LPS.

B. In Vivo

1. Mouse Experimental Autoimmune Encephalomyelitis Assay

The in vivo efficacy of a compound towards autoimmune diseases can bedemonstrated in a mouse model of experimental autoimmuneencephalomyelitis (EAE).

Model Description:

EAE is a useful model for multiple sclerosis (MS), an autoimmune diseaseof the CNS that is caused by immune-cell infiltration of the CNS whitematter. Inflammation and subsequent destruction of myelin causeprogressive paralysis. Like the human disease, EAE is associated withperipheral activation of T cells autoreactive with myelin proteins, suchas myelin basic protein (MBP), proteolipid protein (PLP), or myelinoligodendrocyte protein (MOG). Activated neuroantigen-specific T cellspass the blood-brain barrier, leading to focal mononuclear cellinfiltration and demyelination. EAE can be induced in susceptible mousestrains by immunization with myelin-specific proteins in combinationwith adjuvant. In the SJL mouse model used in these studies, hind limband tail paralysis is apparent by Day 10 after immunization, the peak ofdisease severity can be observed between Days 10 and 14, and a cycle ofpartial spontaneous remission followed by relapse can be observed up toDay 35. The results can demonstrate the potential of a compound tosuppress disease severity and prevent relapse of disease symptoms thatmay be the result of FcγR-mediated cytokine release from immune cells.

Study Protocol:

In the SJL murine model of EAE, each mouse is sensitized withproteolipid protein (PLP)/complete Freund's adjuvant (CFA). (150 μgPLP₁₃₉₋₁₅₁ with 200 μg CFA in 0.05 ml of homogenate on four sites ofhind flank for a total of 0.2 ml emulsion is used to induce EAE). In asuppression protocol, either vehicle or various doses of a test compoundare administered via oral gavage starting on the day of immunization(Day 0). In a treatment protocol, at onset of disease, animals areseparated to achieve groups with a similar mean clinical score at onsetand administered vehicle or various dose frequencies of test compoundsvia oral gavage. In both protocols, clinical scores are monitored daily,and body weights are measured twice weekly.

Determination of Results:

By 10 days after PLP immunization, SJL mice can develop clinical EAE, asevidenced by an increase in their mean clinical scores. The paralyticscore can gradually increase in the animals treated with vehicle onlyfrom the day of immunization (Day 0), and by Day 14 the mean score canreach a peak of about 5.1. At disease peak (e.g., Day 14), the meanclinical score in animals treated with either daily or twice daily canbe significantly reduced. By Day 16, animals can exhibit a partialremission of mean clinical severity, which is a characteristic of theSJL model. The lower clinical scores in animals treated twice daily witha test compound can remain significant throughout the experiment untilthe animals are sacrificed on Day 30. These lower scores throughout thetreatment period are reflected in the significantly lower cumulativedisease index (CDI) and increase in cumulative weight index (CWI).

SJL mice treated with a test compound at disease onset (e.g., Day 11)can show a significant decrease in CDI. Further, there can be a decreasein the number of relapses in animals treated with a test compoundcompared with the number of relapses in animals treated with vehicle.

2. Experimental Autoimmune Encephalomyelitis Animal Model

The in vivo therapeutic efficacy of a compound for treating autoimmunediseases, such as multiple sclerosis, can be assessed in an experimentalautoimmune encephalomyelitis (EAE) animal model.

Animals and EAE Induction:

Female C57BL/6 mice, 8-10 weeks old are immunized subcutaneously in theflanks and mid-scapular region with 200 μg of myelin oligodendrocyteglycoprotein peptide (MOG₃₅₋₅₅) emulsified (1:1 volume ratio) withcomplete Freund's adjuvant (CFA) (containing 4 mg/mL Mycobacteriumtuberculosis). The emulsion is prepared by the syringe-extrusion methodwith two glass Luer-Lock syringes connected by a 3-way stopcock. Miceare also given an intraperitoneal injection of 200 ng pertussis toxin onthe day of immunization and on day two post immunization. Mice areweighed and examined daily for clinical signs of experimental autoimmuneencephalomyelitis (EAE). Food and water is provided ad libitum and onceanimals start to show disease, food is provided on the cage bottom.

Treatment Protocol:

Solutions containing various concentrations of a test compound areadministered by oral gavage twice daily to different treatment groupsstarting from day 3 post-immunization until termination. Dexamethasoneis dissolved in 1×PBS buffer (1 mg/kg) and administered subcutaneouslyonce daily.

Clinical Evaluation:

Mice are scored daily beginning on day 7 post immunization. The clinicalscoring scale is as follows: 0=normal; 1=limp tail or hind limb weakness(defined by foot slips between bars of cage top while walking); 2=limptail and hind limb weakness; 3=partial hind limb paralysis (defined asno weight bearing on hind limbs but can still move one or both hindlimbs to some extent); 4=complete hind limb paralysis; 5=moribund state(includes forelimb paralysis) or death. In some embodiments, compound 1(methyl (E)-3-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)acrylate)significantly prevents the onset of disease paralysis when dosed at 60mg/kg beginning on the day of immunization.

3. Animal Model to Assess Therapeutic Efficacy in Treating Psoriasis

The in vivo therapeutic efficacy of a compound for treating psoriasiscan be assessed in an experimental animal model. For example, thesevere, combined immunodeficient (SCID) mouse model can be used toevaluate the efficacy of compounds for treating psoriasis in humans.

SCID mice are used as tissue recipients. One biopsy for each normal orpsoriatic volunteer is transplanted onto the dorsal surface of arecipient mouse. Treatment is initiated 1 to 2 weeks aftertransplantation. Animals with the human skin transplants are dividedinto treatment groups. Animals are treated twice daily for 14 days. Atthe end of treatment, animals are photographed and then euthanized. Thetransplanted human tissue along with the surrounding mouse skin issurgically removed and fixed in 10% formalin and samples obtained formicroscopy. Epidermal thickness is measured. Tissue sections are stainedwith an antibody to the proliferation-associated antigen Ki-67 and withan anti-human CD3⁺ monoclonal antibody to detect human T lymphocytes inthe transplanted tissue. Sections are also probed with antibodies toc-myc and β-catenin. A positive response to treatment is reflected by areduction in the average epidermal thickness of the psoriatic skintransplants. A positive response is also associated with reducedexpression of Ki-67 in keratinocytes.

4. Animal Model to Assess Therapeutic Efficacy in Treating MultipleSclerosis

The in vivo therapeutic efficacy of a compound for treating multiplesclerosis can be assessed in an experimental animal model.

Experiments are conducted on female C57BL/6 mice aged 4-6 weeks andweighing 17-20 g. Experimental autoimmune encephalomyelitis (EAE) isactively induced using ≥95% pure synthetic myelin oligodendrocyteglycoprotein peptide 35-55 (MOG₃₅-5₅, MEVGWYRSPFSRVVHLYRNGK) (SEQ ID NO:1). Each mouse is anesthetized and receives 200 μg of MOG peptide and 15μg of Saponin extract from Quilija bark emulsified in 100 μL ofphosphate-buffered saline. A 25 μL volume is injected subcutaneouslyover four flank areas. Mice are also intraperitoneally injected with 200ng of pertussis toxin in 200 μL of PBS. A second, identical injection ofpertussis toxin is given after 48 h.

A test compound is administered at varying doses. Control animalsreceive 25 μL of DMSO. Daily treatment extends from day 26 to day 36post-immunization. Clinical scores are obtained daily from day 0post-immunization until day 60. Clinical signs are scored using thefollowing protocol: 0, no detectable signs; 0.5, distal tail limpness,hunched appearance and quiet demeanor; 1, completely limp tail; 1.5,limp tail and hind limb weakness (unsteady gait and poor grip with hindlimbs); 2, unilateral partial hind limb paralysis; 2.5, bilateral hindlimb paralysis; 3, complete bilateral hind limb paralysis; 3.5, completehind limb paralysis and unilateral forelimb paralysis; 4, totalparalysis of hind limbs and forelimbs.

Inflammation and demyelination are assessed by histology on sectionsfrom the CNS of EAE mice. Mice are euthanized after 30 or 60 days andwhole spinal cords are removed and placed in 0.32 M sucrose solution at4° C. overnight. Tissues are prepared and sectioned. Luxol fast bluestain is used to observe areas of demyelination. Haematoxylin and eosinstaining is used to highlight areas of inflammation by darkly stainingthe nuclei of mononuclear cells. Immune cells stained with H&E arecounted in a blinded manner under a light microscope. Sections areseparated into gray and white matter and each sector is counted manuallybefore being combined to give a total for the section. T cells areimmunolabeled with anti-CD3⁺ monoclonal antibody. After washing,sections are incubated with goat anti-rat HRP secondary antibody.Sections are then washed and counterstained with methyl green.Splenocytes isolated from mice at 30 and 60 days post-immunization aretreated with lysis buffer to remove red blood cells. Cells are thenresuspended in PBS and counted. Cells at a density of about 3×10⁶cells/mL are incubated overnight with 20 μg/mL of MOG peptide.Supernatants from stimulated cells are assayed for IFN-γ protein levelsusing an appropriate mouse IFN-γ immunoassay system.

Research Applications

Since subject compounds find use for the treatment of autoimmune andinflammatory diseases and disorders, such compounds are also useful asresearch tools. The present disclosure also provides a method for usingthe subject compounds as a research tool for studying a biologicalsystem or sample, or for discovering new chemical compounds that can beused for the treatment of autoimmune and inflammatory diseases anddisorders, such as psoriasis or multiple sclerosis.

The disclosure provides for a method of studying a biological system orsample known to be associated with an autoimmune or inflammatory diseaseor disorder, the method comprising: (a) contacting the biological samplewith a compound of the present disclosure or a salt or solvate orstereoisomer thereof; and (b) determining the efficacy of the compoundon treating the biological sample.

Any suitable biological sample can be employed in such studies which canbe conducted either in vitro or in vivo. Representative biologicalsamples suitable for such studies include, but are not limited to,cells, cellular extracts, plasma membranes, tissue samples, isolatedorgans, mammals (such as mice, rats, guinea pigs, rabbits, dogs, pigs,humans, and so forth), and the like, with mammals being of particularinterest.

When used as a research tool, a biological sample is typically contactedwith a pharmaceutically effective amount of a subject compound. Afterthe biological sample is exposed to the compound, the effects of thecompound are determined using conventional procedures and equipment,such as the assays disclosed herein. Exposure encompasses contacting thebiological sample with the compound or administering the compound to asubject. The determining step can involve measuring a response (aquantitative analysis) or can involve making an observation (aqualitative analysis). Measuring a response involves, for example,determining the effects of the compound on the biological sample usingconventional procedures and equipment, such as radioligand bindingassays and measuring ligand-mediated changes in functional assays. Theassay results can be used to determine the activity level as well as theamount of compound necessary to achieve the desired result, that is, apharmaceutically effective amount.

Additionally, the subject compounds can be used as research tools forevaluating other chemical compounds, and thus are also useful inscreening assays to discover, for example, new compounds useful for thetreatment of an autoimmune or inflammatory disease or disorder. In thismanner, a subject compound can be used as a standard in an assay toallow comparison of the results obtained with a test compound and withthe subject compounds to identify those test compounds that have aboutequal or superior activity, if any. For example, EC₅₀ data for a testcompound or a group of test compounds is compared to the EC₅₀ data for asubject compound to identify those test compounds that have the desiredproperties, for example, test compounds having an EC₅₀ about equal orsuperior to a subject compound, if any.

This aspect includes, as separate embodiments, both the generation ofcomparison data (using the appropriate assays) and the analysis of testdata to identify test compounds of interest. Thus, a test compound canbe evaluated in a biological assay, by a method comprising the steps of:(a) conducting a biological assay with a test compound to provide afirst assay value; (b) conducting the biological assay with a subjectcompound to provide a second assay value; where step (a) is conductedeither before, after or concurrently with step (b); and (c) comparingthe first assay value from step (a) with the second assay value fromstep (b). The assays that can be used for generation of comparison dataare disclosed herein, such as the mouse EAE assays.

General Synthetic Procedures

Many general references providing commonly known chemical syntheticschemes and conditions useful for synthesizing the disclosed compoundsare available (see, e.g., Smith and March, March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, Fifth Edition,Wiley-Interscience, 2001; or Vogel, A Textbook of Practical OrganicChemistry, Including Qualitative Organic Analysis, Fourth Edition, NewYork: Longman, 1978).

Compounds as described herein can be purified by any purificationprotocol known in the art, including chromatography, such as HPLC,preparative thin layer chromatography, flash column chromatography andion exchange chromatography. Any suitable stationary phase can be used,including normal and reversed phases as well as ionic resins. In certainembodiments, the disclosed compounds are purified via silica gel and/oralumina chromatography. See, e.g., Introduction to Modern LiquidChromatography, 2nd Edition, ed. L. R. Snyder and J. J. Kirkland, JohnWiley and Sons, 1979; and Thin Layer Chromatography, ed E. Stahl,Springer-Verlag, New York, 1969.

During any of the processes for preparation of the subject compounds, itmay be necessary and/or desirable to protect sensitive or reactivegroups on any of the molecules concerned. This may be achieved by meansof conventional protecting groups as described in standard works, suchas J. F. W. McOmie, “Protective Groups in Organic Chemistry”, PlenumPress, London and New York 1973, in T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis”, Third edition, Wiley, New York1999, in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer),Academic Press, London and New York 1981, in “Methoden der organischenChemie”, Houben-Weyl, 4^(th) edition, Vol. 15/1, Georg Thieme Verlag,Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, “Aminosauren, Peptide,Proteine”, Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982,and/or in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide andDerivate”, Georg Thieme Verlag, Stuttgart 1974. The protecting groupsmay be removed at a convenient subsequent stage using methods known fromthe art.

The subject compounds can be synthesized via a variety of differentsynthetic routes using commercially available starting materials and/orstarting materials prepared by conventional synthetic methods. All ofthe compounds described herein can be prepared by adaptation of thesemethods.

Stereoisomers of the compounds can be isolated by procedures known tothose skilled in the art. The individual stereoisomers may be obtained,for instance, by a resolution technique or by chromatography techniques(e.g., silica gel chromatography, chiral chromatography, etc.).

Although the synthetic schemes discussed herein may not illustrate theuse of protecting groups, skilled artisans will recognize that in someinstances certain substituents may include functional groups requiringprotection. The exact identity of the protecting group used will dependupon, among other things, the identity of the functional group beingprotected and the reaction conditions used in the particular syntheticscheme, and will be apparent to those of skill in the art. Guidance forselecting protecting groups, their attachment and removal suitable for aparticular application can be found, for example, in Greene & Wuts,supra.

In certain embodiments, in the above methods, the method furtherincludes separating isomers with a resolution technique. In certainembodiments, in the above methods, the method further includesseparating isomers with chiral chromatography. In certain embodiments,the disclosure provides a method for preparing an optically activecompound.

In some embodiments, the above methods further include the step offorming a salt of a compound disclosed herein. Embodiments are directedto the other processes described herein, and to the product prepared byany of the processes described herein.

In some instances, the subject compounds are prepared according to oneof the generic synthetic Schemes A-D depicted below.

where each R′ and R″ independently can be any convenient groups asdescribed herein. In some cases, R′ is alkyl or substituted alkyl. Insome cases, R″ is alkyl (e.g., methyl), substituted alkyl, heteroaryl(e.g., 3-pyridyl), substituted heteroaryl, aryl or substituted aryl.

In some instances, the subject compounds are prepared via the strategydepicted in Scheme A via reaction of a substituted acetylenic sulfonewith a 1-substituted-1H-tetrazol-5(4H)-one. Acetylenic sulfones whichfind use in the preparation of the subject compounds via Scheme A can beprepared by adapting those methods described in U.S. Publication No.2011/0281177, the disclosure of which is incorporated herein byreference. 1-Substituted-1H-tetrazol-5(4H)-ones can be prepared usingany convenient procedure.

where each R′ and R″ independently can be any convenient groups asdescribed herein. In some cases, R′ is alkyl or substituted alkyl. Insome cases, R″ is alkyl (e.g., methyl), substituted alkyl, heteroaryl(e.g., 3-pyridyl), substituted heteroaryl, aryl or substituted aryl.

In some instances, the subject compounds are prepared via the strategydepicted in Scheme B via reaction of a dimeric vinyl sulfone and a1-substituted-1H-tetrazol-5(4H)-one. Dimeric vinyl sulfones which finduse in the preparation of the subject compounds via Scheme B can beprepared by adapting those methods described by Tiecco et al. (J. Org.Chem. 1983, 48, 4795-4800), the disclosure of which is incorporatedherein by reference. 1-Substituted-1H-tetrazol-5(4H)-ones can beprepared using any convenient procedure.

where X is a leaving group (e.g., a halogen) and each R′ and R″independently can be any convenient groups as described herein. In somecases, R′ is alkyl or substituted alkyl. In some cases, R″ is alkyl(e.g., methyl), substituted alkyl, heteroaryl (e.g., 3-pyridyl),substituted heteroaryl, aryl or substituted aryl.

In some instances, the subject compounds are prepared via the strategydepicted in Scheme C via reaction of a monomeric vinyl sulfone with a1-substituted-1H-tetrazol-5(4H)-one. Vinyl sulfones which find use inthe preparation of the subject compounds via Scheme C can be prepared byadapting those methods described by Guan et al. (Synthesis 2007, 10,1465-70), the disclosure of which is incorporated herein by reference.1-Substituted-1H-tetrazol-5(4H)-ones can be prepared using anyconvenient procedure.

where each R′ and R″ independently can be any convenient groups asdescribed herein. In some cases, R′ is alkyl or substituted alkyl. Insome cases, R″ is alkyl (e.g., methyl), substituted alkyl, heteroaryl(e.g., 3-pyridyl), substituted heteroaryl, aryl or substituted aryl.

In some instances, the subject compounds are prepared via the strategydepicted in Scheme D from a sulfonyl acrylic acid which is convertedinto a tetrazolone intermediate and then further substituted at the1-position with any convenient substituent (R″). The sulfonyl acrylicacid starting material (e.g., (E)-3-(methylsulfonyl)acrylic acid) whichfinds use in the preparation of the subject compounds via Scheme D canbe prepared by adapting those methods described by Guan et al.(Synthesis 2007, 10, 1465-70), the disclosure of which is incorporatedherein by reference. The sulfonyl acrylic acid can be converted to atetrazolone using a variety of methods. In some cases, the sulfonylacrylic acid is activated (e.g., to an acyl chloride or an acyl azide)which is further reacted with an azide reagent (e.g., trimethylsilylazide, TMS-N₃) to produce the intermediate 1H-tetrazol-5(4H)-one. Forexample, the conversion of sulfonyl acrylic acid can be achieved byreaction with the reagent diphenylphosphoryl azide followed bytrimethylsilyl azide. Alternatively, the conversion of sulfonyl acrylicacid can be achieved by reaction with the reagent oxalyl chloridefollowed by trimethylsilyl azide.

The tetrazolone intermediate can then be further substituted at the1-position using a variety of methods. In some cases, substitution canbe achieved using an alkyl halide reagent under basic conditions. Insome cases, a nucleophilic aromatic substitution reaction can beperformed to include an aryl or heteroaryl substituent at the1-position.

In some embodiments of the synthetic schemes A-D described herein R′ isan alkyl (e.g., methyl) or a substituted alkyl (e.g., isopropyl ortert-butyl). In some embodiments of the synthetic schemes A-D describedherein R′ is an aryl (e.g., phenyl) or a substituted aryl (e.g.,4-methylphenyl).

Schemes A-D described herein may be used to synthesize Nrf2 activatingcompounds as disclosed herein. Subsequent reaction of the Nrf2activating compound with a second moiety can be used to synthesize aprodrug as described herein. Examples of such synthetic routes that canbe used to synthesize the prodrugs disclosed herein are described in theExamples below.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the embodiments, and are not intended to limit the scope ofwhat the inventors regard as their invention nor are they intended torepresent that the experiments below are all or the only experimentsperformed. Efforts have been made to ensure accuracy with respect tonumbers used (e.g. amounts, temperature, etc.) but some experimentalerrors and deviations should be accounted for. As will be understood, bythose of skill in the art of organic synthesis and medicinal chemistrythe specific conditions set forth below are exemplary and can be variedor adapted to other reagents and products in routine fashion. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Celsius, andpressure is at or near atmospheric. Standard abbreviations may be used.

Example 1: Synthesis ofN⁵-((2R)-1-((Carboxymethyl)amino)-3-((1-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-2-tosylethyl)thio)-1-oxopropan-2-yl)-L-glutamine(Compound 1)

To a solution of(E)-1-methyl-4-(2-tosylvinyl)-1,4-dihydro-5H-tetrazol-5-one (100, 100mg, 0.36 mmol), glutathione (GSH) (200, 110 mg, 0.36 mmol) in MeOH/H₂O(5 mL, 1:1), TEA (5 μL, 3.6 mg, 36 μmol)) was added. The heterogeneousreaction mixture was then allowed to stir at 60° C. for 2 days, cooleddown to room temperature and concentrated to give a white solid. Reversephase chromatography provided 101 mg (48%) of 1:1 diastereomeric mixtureofN-((2R)-1-((carboxymethyl)amino)-3-((1-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-2-tosylethyl)thio)-1-oxopropan-2-yl)-L-glutamine(1) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 7.73-7.65 (m, 2H), 7.44-7.36 (m, 2H), 5.93(dd, J=11.3, 2.3 Hz, 0.5H), 5.80 (dd, J=11.4, 2.6 Hz, 0.5H), 4.81 (dd,J=9.5, 4.6 Hz, 0.5H), 4.49 (dd, J=8.8, 5.0 Hz, 0.5H), 4.39 (ddd, J=14.3,11.3, 2.8 Hz, 1H), 3.93 (dd, J=4.4, 2.5 Hz, 0.5H), 3.89 (dd, J=4.5, 2.5Hz, 0.5H), 3.88 (s, 1H), 3.86 (d, J=2.3 Hz, 1H), 3.69 (t, J=5.9 Hz,0.5H), 3.63 (t, J=6.2 Hz, 0.5H), 3.46 (s, 3H), 3.20 (dd, J=14.2, 5.0 Hz,0.5H), 3.05 (dd, J=14.4, 4.6 Hz, 0.5H), 2.94 (dd, J=14.2, 8.8 Hz, 0.5H),2.74 (dd, J=14.4, 9.5 Hz, 0.5H), 2.57 (t, J=6.2 Hz, 1H), 2.49 (q, J=6.7Hz, 1H), 2.45 (s, 3H), 2.12 (dp, J=18.7, 6.6 Hz, 2H).

¹³C NMR (101 MHz, CD₃OD) δ 175.74, 175.15, 173.78, 173.45, 173.35,172.32, 172.26, 151.57, 151.30, 147.09, 147.07, 136.99, 136.94, 131.18,129.46, 57.96, 57.53, 56.67, 55.54, 55.04, 54.38, 53.05, 42.44, 42.43,34.47, 33.93, 33.04, 33.01, 31.79, 31.72, 27.74, 27.48, 21.73.

MS m/e: 588 (M⁺H)⁺.

Example 2: Synthesis ofN⁵-((2R)-1-((Carboxymethyl)amino)-3-((1,4-dimethoxy-1,4-dioxobutan-2-yl)thio)-1-oxopropan-2-yl)-L-glutamine(Compound 11)

To a solution of dimethyl fumarate (400, 100 mg, 0.69 mmol), GSH (200,215 mg, 0.70 mmol) in MeOH/H₂O (5 mL, 1:1), TEA (10 μL, 7.3 mg, 72μmol)) was added. The heterogeneous reaction mixture was then allowed tostir at 60° C. for 2 hrs. and at room temperature for 3 days, cooleddown to room temperature and concentrated to give a white solid. Reversephase chromatography provided 139 mg (44%) of 1:1 diastereomeric mixtureofN⁵-((2R)-1-((carboxymethyl)amino)-3-((1-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-2-tosylethyl)thio)-1-oxopropan-2-yl)-L-glutamine(11) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 8.15 (s, 1H), 4.67-4.61 (m, 1H), 3.90 (s, 2H),3.81-3.77 (m, 1H), 3.75, 3.74 (2s, 3H), 3.67, (s, 3H), 3.67 (t, J=6.3Hz, 1H), 3.23 (ddd, J=14.1, 9.0, 5.1 Hz, 1H), 3.03-2.84 (m, 2H), 2.74(dd, J=36.4, 5.5 Hz, 0.5H), 2.74 (dd, J=5.9, 2.3 Hz, 0.5H), 2.56-2.52(m, 2H), 2.21-2.06 (m, 2H).

MS m/e: 452 (M⁺H)⁺.

Example 3: Synthesis ofN⁵-((2R)-1-((Carboxymethyl)amino)-3-((3-methoxy-3-oxo-1-(5-oxo-4-(pyridin-3-yl)-4,5-dihydro-1H-tetrazol-1-yl)propyl)thio)-1-oxopropan-2-yl)-L-glutamine(Compound 2)

To a solution of methyl(E)-3-(5-oxo-4-(pyridin-3-yl)-4,5-dihydro-1H-tetrazol-1-yl)acrylate(600, 100 mg, 0.4 mmol), GSH (200, 0.125 mg, 0.41 mmol) in MeOH/H₂O (5mL, 1:1), TEA (6 μL, 4.4 mg, 43 μmol)) was added. The heterogeneousreaction mixture was then allowed to stir at 60° C. for 3 days, cooleddown to room temperature and concentrated to give a white solid. Reversephase chromatography provided 75 mg (33%) of 1:1 diastereomeric mixtureofN⁵-((2R)-1-((carboxymethyl)amino)-3-((3-methoxy-3-oxo-1-(5-oxo-4-(pyridin-3-yl)-4,5-dihydro-1H-tetrazol-1-yl)propyl)thio)-1-oxopropan-2-yl)-L-glutamine(2) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 9.17 (t, J=2.7 Hz, 1H), 8.61 (dd, J=4.7, 1.2Hz, 1H), 8.42-8.39, (m, 1H), 8.13 (s, 1H), 7.64 (d, J=5.1 Hz, 0.5H),7.62 (d, J=4.7 Hz, 0.5H), 5.95-5.86 (m, 1H), 4.63-4.59 (m, 0.5H), 3.90(s, 1H), 3.88 (s, 1H), 3.69 (s, 3H), 3.65 (t, J=6.3 Hz, 0.5H), 3.61 (t,J=6.3 Hz, 0.5H), 3.47-3.38 (m, 1H), 3.34-3.21 (m, 2H), 3.06 (dd, J=14.1,9.0 Hz, 0.5H), 2.89 (dd, J=14.5, 9.4 Hz, 0.5H), 2.57-2.47 (m, 2H),2.18-2.14 (m, 2H).

MS m/e: 555 (M⁺H)⁺.

Example 4: Synthesis of MethylN-Acetyl-S-(1-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(phenylsulfonyl)ethyl)-L-cysteinate(Compound 3)

To a solution of(E)-4-methyl-2-(2-(phenylsulfonyl)vinyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(800, 400 mg, 1.5 mmol), N—Ac-L-Cys-OMe (900, 300 mg, 1.7 mmol) inMeOH/H₂O (3 mL, 1:1), TEA (21 μL, 15.2 mg, 150 μmol)) was added. Theheterogeneous reaction mixture was then allowed to stir at 50° C. for 2days, cooled down to room temperature and concentrated to give a whitesolid. Column chromatography, eluting with 2-10% MeOH/DCM, provided 506mg (76%) of 3:2 diastereomeric mixture of methylN-acetyl-S-(1-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(phenylsulfonyl)ethyl)-L-cysteinate(3) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.91-7.83 (m, 2H), 7.67-7.60 (m, 1H),7.56-7.51 (m, 2H), 7.21 (s, 0.4H), 7.18 (s, 0.6H), 7.02 (d, J=8.2 Hz,0.4H), 6.49 (d, J=7.0 Hz, 0.6H), 5.91 (dd, J=10.9, 2.4 Hz, 0.4H), 5.83(dd, J=10.4, 2.8 Hz, 0.6H), 4.90-4.78 (m, 1H), 4.23 (ddd, J=14.7, 10.6,2.9 Hz, 1H), 3.76 (s, 1.8H), 3.75 (s, 1.2H), 3.54 (dd, J=14.7, 2.9 Hz,0.6H), 3.48 (dd, J=14.7, 2.4 Hz, 0.4H), 3.22 (s, 1.2H), 3.17 (s, 1.8H),3.13 (dd, J=14.1, 4.6 Hz, 0.6H), 3.03-2.97 (m, 0.4H), 2.95 (dd, J=14.2,5.6 Hz, 0.6H), 2.87 (dd, J=14.7, 7.2 Hz, 0.4H), 2.10 (s, 1.2H), 2.07 (s,1.8H).

¹³C NMR (101 MHz, CDCl₃) δ 170.95, 170.84, 170.68, 170.33, 153.41,152.85, 138.79, 138.74, 137.52, 137.29, 134.07, 134.01, 129.32, 129.26,128.61, 128.54, 57.91, 57.76, 54.44, 54.09, 53.41, 53.07, 53.00, 52.61,32.96, 32.42, 29.17, 29.05, 23.27, 23.25.

MS m/e: 443 (M⁺H)⁺.

Example 5: Synthesis ofN-Acetyl-S-(1-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(phenylsulfonyl)ethyl)-L-cysteine(Compound 4)

To a solution of(E)-4-methyl-2-(2-(phenylsulfonyl)vinyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(800, 50 mg, 0.19 mmol), N—Ac-L-Cys-OH (1100, 35 mg, 0.21 mmol) inMeOH/H₂O (3 mL, 1:1), TEA (150 μL, 110 mg, 1.1 mmol)) was added. Theheterogeneous reaction mixture was then allowed to stir at 50° C. for 2days, cooled down to room temperature and concentrated to give a whitesolid. Reverse phase chromatography provided 49 mg (61%) of 2:1diastereomeric mixture ofN-acetyl-S-(1-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(phenylsulfonyl)ethyl)-L-cysteine(4) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (d, J=8.2 Hz, 0.66H), 8.16 (d, J=7.9Hz, 0.34H), 7.76-7.65 (m, 3H), 7.63 (s, 0.34H), 7.62 (s, 0.66H),7.61-7.54 (m, 2H), 5.59 (ddd, J=11.1, 4.6, 2.3 Hz, 1H), 4.39-4.14 (m,2H), 3.86 (td, J=14.5, 2.4 Hz, 1H), 2.99 (s, 1H), 2.98 (s, 2H),2.94-2.77 (m, 1.34H), 2.72 (dd, J=13.5, 8.4 Hz, 0.66H), 1.83 (s, 2H),1.82 (s, 1H).

¹³C NMR (101 MHz, DMSO-d₆) δ 171.66, 171.65, 169.24, 169.23, 152.07,152.00, 138.42, 138.33, 138.22, 138.17, 133.87, 133.83, 128.99, 128.95,127.76, 127.65, 56.78, 56.64, 53.49, 53.20, 52.25, 51.30, 31.67, 31.52,28.28, 28.25, 22.33, 22.30.

MS m/e: 429 (M⁺H)⁺.

Example 6: General Synthesis of Prodrug Compounds

A mixture of methyl(E)-3-(5-oxo-4-(pyridin-3-yl)-4,5-dihydro-1H-tetrazol-1-yl)acrylate (0.1g, 0.40 mmol), methyl acetyl-L-cysteinate (0.08 g, 0.44 mmol), andtriethylamine (6 μl, 0.04 mmol) in methanol (2 mL) was stirred at roomtemperature for 5 h. The reaction mixture was then concentrated underreduced pressure to give a residue, which was purified by chromatographyeluting with ethyl acetate/hexanes (7/3) to provide methylN-acetyl-S-(3-methoxy-3-oxo-1-(5-oxo-4-(pyridin-3-yl)-4,5-dihydro-1H-tetrazol-1-yl)propyl)-L-cysteinate(9) as an off-white solid (0.12 g, 73%).

¹H NMR (CD₃OD, 400 MHz) δ 9.14 (m, 1H), 8.06 (m, 1H), 8.36 (m, 1H), 7.62(m, 1H), 5.85 (m, 1H), 4.68 (m, 1H), 3.67 (m, 6H), 3.39 (m, 1H), 3.23(m, 2H), 3.06 (m, 1H), 1.96 (m, 3H).

¹³C NMR (CD₃OD, 100 MHz) δ 171.84, 171.67, 170.74, 170.66, 169.33,169.24, 148.27, 148.22, 148.17, 140.31, 140.15, 131.81, 127.67, 127.49,124.31, 57.24, 56.89, 56.14, 52.29, 51.84, 51.62, 51.61, 37.68, 37.11,33.05, 32.23, 20.92, 20.87, 16.94.

MS m/e: 425.1 (M⁺H)⁺.

Compounds 10 and 12 were also prepared using the general syntheticscheme described above for Compound 9.

MethylN-acetyl-S-(1-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-2-tosylethyl)-L-cysteinate(Compound 10)

¹H NMR (CDCl₃, 400 MHz) δ 7.71 (m, 2H), 7.33 (m, 2H), 6.52 (m, 1H), 5.82(m, 1H), 4.86 (m, 1H), 4.31 (m, 1H), 3.76 (m, 3H), 3.59 (m, 1H), 3.50(m, 3H), 3.08 (m, 2H), 2.44 (s, 3H), 2.06 (m, 3H).

MS m/e: 458.2 (M⁺H)⁺.

Dimethyl2-(((R)-2-(Acetyl-λ²-azaneyl)-3-methoxy-3-oxopropyl)thio)succinate(Compound 12)

¹H NMR (CDCl₃, 400 MHz) δ 6.62 (m, 1H), 4.92 (m, 1H), 3.73 (m, 10H),3.22 (m, 1H), 3.11 (m, 1H), 2.95 (m, 1H), 2.67 (m, 1H), 2.06 (m, 3H).

¹³C NMR (CDCl₃, 100 MHz) δ 171.92, 171.88, 171.20, 170.88, 170.82,170.80, 170.11, 169.92, 52.79, 52.75, 52.72, 52.22, 52.13, 52.04, 51.96,42.26, 41.97, 36.39, 35.86, 34.26, 34.02, 23.05, 22.30.

MS m/e: 322.1 (M⁺H)⁺.

Example 7: Biological Activity of Compounds Autoimmune Encephalitis(EAE) In Vivo Assay

Compounds disclosed herein are tested in an autoimmune encephalitis(EAE) in vivo assay in mice according to the methods described above inthe paragraph entitled B.2. Experimental Autoimmune EncephalomyelitisAnimal Model. For example, compounds of the present disclosure areuseful for preventing the onset of disease paralysis when dosed at 60mg/kg beginning on the day of immunization.

NrF2 Activation in a Whole Cell Nuclear Translocation Assay

Compounds are tested in a NrF2 (Nuclear factor (erythroid-derived2)-like 2) translocation assay by adapting the methods set forth in U.S.Pat. No. 8,101,373, the disclosure of which is incorporated herein byreference. A result of NrF2 activation in the assay by the presentcompounds is an indication of their anti-inflammatory activity.

Monomethyl fumarate and dimethyl fumarate have NrF2 activation withEC50s of about 127 and 7.9 micromolar, respectively. Examples ofcompounds disclosed herein may show comparable activity to monomethylfumarate and dimethyl fumarate in the NrF2 translocation assay. Inaddition to monomethyl fumarate and dimethyl fumarate, bardoxolonemethyl may be used as a positive control.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A compound of formula (I):

wherein: R² is selected from the group consisting of sulfonyl, carboxyl, carboxyl ester, and aminoacyl; R³ is selected from the group consisting of an active agent, an antioxidant, an amino acid, an amino acid derivative, a peptide, and a peptide derivative; R⁴ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; X¹ and X² are each independently selected from N and CH, wherein at least one of X¹ and X² is N; and n is an integer from 1 to 6, or a salt or a stereoisomer thereof.
 2. The compound of claim 1, wherein R² is sulfonyl or carboxyl ester.
 3. The compound of claim 1, wherein the compound is a compound of formula (II):

wherein: R³ is selected from the group consisting of an active agent, an antioxidant, an amino acid, an amino acid derivative, a peptide, and a peptide derivative; R⁴ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R⁵ is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; X¹ and X² are each independently selected from N and CH, wherein at least one of X¹ and X² is N; and n is an integer from 1 to 6, or a salt or a stereoisomer thereof.
 4. The compound of claim 3, wherein R⁵ is aryl or substituted aryl.
 5. The compound of claim 1, wherein n is
 1. 6. The compound of claim 1, wherein n is
 2. 7. The compound of claim 1, wherein R³ is glutathione.
 8. The compound of claim 1, wherein R³ is an amino acid or an amino acid derivative.
 9. The compound of claim 1, wherein X¹ is N and X² is N.
 10. The compound of claim 1, wherein X¹ is N and X² is CH.
 11. The compound of claim 1, wherein the compound is selected from the group consisting of:


12. An isolated compound, wherein the isolated compound is selected from the group consisting of:


13. A pharmaceutical composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier.
 14. A method of treating a disease or disorder in a subject in need thereof, the method comprising: administering to the subject a pharmaceutically effective amount of a compound of claim 1 sufficient to treat the disease or disorder in the subject, wherein the disease or disorder is an autoimmune disease or an inflammatory disease.
 15. The method of claim 14, wherein the disease or disorder is psoriasis or multiple sclerosis. 